Cytostatic drugs in infants: A review on pharmacokinetic data in infants
Article Outline
- Abstract
- Introduction
- Other general factors in infant cytostatic treatment
- Alkylating agents
- Antimetabolites
- Antimitotic drugs
- Topoisomerase inhibitors
- Anti-tumor antibiotics
- Miscellaneous drugs
- Formulation
- Conclusion
- References
- Copyright
Abstract
Below a certain age protocols in pediatric oncology on cytostatic drug therapy advise use, of other parameters such as weight for dosing; this instead of the most conventional parameter, i.e. body surface area. In infants it is not uncommon that additional reductions are put on top of this for each cytostatic drugs to be administered. The rationale behind this is often lacking. Differences related to the ontogeny of absorption, distribution, metabolism and excretion are often not mentioned. Considering characteristics, such as lipophilia, ionization in relation to pH and size of the molecule and linking these characteristics with age related shifts in the gastrointestinal tract, composition of the body and renal function; predictions on pharmacokinetics (PK) in these infants can to a certain extent be made. More difficult are the shifts in activity of phase I and II enzymes, which are often not known for a specific product. In this review data on the ontogeny of relevant pharmacokinetic pathways in relation to the various cytostatic drugs and data from pharmacokinetic (PK) studies in infants are presented.
This review shows that the administration of cytostatic drugs in infants is often based on limited or even no data at all. Based on such a lack of evidence on treatment of infants with cancer; it should be mandatory that in each infant treated with cytostatic drugs pharmacokinetic data are collected. Compiling these data in a global database would enable evidence-based drug therapy in infants with malignancies, resulting in a more effective treatment with less toxicity in this vulnerable population.
Keywords: Cytostatic drugs, Infant, Pharmacotherapy, Pharmacokinetics, Oncology, Children, Infants, Ontogeny, Metabolism, Allometric scaling
Introduction
Adult cancer treatment is often based on the assumption that each individual person metabolizes cytostatic drugs with the same efficiency. Individual differences might however either result in increased toxicity or less efficacy. Increased toxicity is dealt with in a pragmatic way: dose reductions are often applied in the next courses. Increased metabolism resulting in an increased relapse rate is often not noted. Individual differences are, however, currently often linked to pharmacogenetic data.[1], [2] These pharmacogenetic factors are in pediatric pharmacotherapy superimposed on developmental differences in relation to age, weight and body surface area. Especially in infancy substantial deviations in the pharmacokinetics (PK) of drugs are noted. Most pronounced are the PK changes during the first months of life. The response to the various drugs (pharmacodynamics) may be different in children with the same type of malignancy. However, in this review we will not focus on the pharmacodynamics of the cytostatic drugs.
Reports on the PK of cytostatic drugs administered to infants are very limited and often confined to a few studies and case reports in this age group; often only dealing with to adverse effects. Examples of cytostatic drugs are reports on the excessive neurotoxicity of vincristine, resulting in hypotonia, feeding difficulties and paralysis of respiratory muscles.[1], [2], [3] Unexpected side effects during chemotherapeutic treatment of Wilms’ tumors have resulted in the recommendation to decrease the vincristine dosages to 50.4 Still the situation on increased side-effects in infants has not been resolved.5
In many protocols and some textbooks the evidence for dose recommendations is less clear and sources often are not indicated.6 In most protocols dose reductions are proposed in infants, either given as a percentage according to age or as calculations based on body weight instead of the body surface area. Since liver volume is correlated with body surface area and not to weight dosing according to body surface area would be more relevant for drugs with hepatic clearance only. However, the impact of ontogeny on the metabolic capacity is completely neglected this way.7 Even in a specific protocol for infants with acute lymphoblastic leukemia (ALL) substantial dose reductions are mentioned irrespective of the drug involved.[8], [9] The pharmacokinetic relevance of this is doubtful.[10], [11] Although in pediatric oncology the age limit separating infancy from the toddler period is usually at 12
months, this review provides data on cytostatic drugs in children below the age of 2years because these data are relevant and data in infants <1year were often too scarce. Before discussing the various cytostatic drugs a summary is given on developmental changes relevant for the PK of cytostatic drugs.
Absorption
The majority of cytostatic drugs are administered intravenously to infants. In a few patients oral administration is used. These infants mainly suffer from leukemia and are treated with 6-mercaptopurine and methotrexate during the maintenance phase of their treatment. Since there are currently no pharmaceutical formulations for oral use in infants marketed, extemporaneous formulations are standard of care. The quality of these extemporaneous formulations is not secured and in case of tablets used as a starting point, the matrix of excipients and the breaking strength are essential variables.12 Developmental factors important for the oral use are gastric acid production, pepsin secretion, and gastric emptying. Secretion of both gastric acid and pepsin are strongly decreased in infancy. In addition this secretion is influenced by enteral feeding.[13], [14] For phenobarbital it has been shown that higher dosages are needed. For cytostatic drugs there are no data available.15 As a result of this low acid and pepsin secretion increased absorption related to state of ionization of weak acids (such as methotrexate), is to be expected. Gastrointestinal motility is decreased in infancy and gastric emptying is initially decreased.[16], [17] Since both methotrexate and 6-mercaptopurine (being the most often administered orally administered drugs) are water soluble, changes in biliary function and biliary composition are less important in infants with a malignant disease.[18], [19] In general it is assumed that intestinal surface is reduced in early childhood, despite the fact that if using anthropometric data, the intestinal surface exceeds adult values.[20], [21] Differences in intestinal bacterial flora can be of major influence on pharmacokinetics (PK).22 As a result the formation of the methotrexate metabolite, DAMPA, which is produced by bacterial enzymes from methotrexate will be influenced by the kind of feeding. The drug-metabolizing enzyme function of the intestinal wall in infants differs substantially from adults. Epoxide hydrolase and glutathione peroxidase show little age dependency in contrast to CYP1A1, which expression was shown to increase with age.23 In contrast, young infants have a significant expression of CYP3A4 and P-gp m-RNA.24 But activity may be, despite expression, significantly different. As such the intestinal CYP3A4 activity was shown to increase during childhood.25 It should be mentioned that both data on expression and drug-specificity of enzymes cannot be extrapolated from the liver to the intestine. In most infants with a malignancy abnormal gastro-intestinal absorption will not be recognized, since only a very limited number of drugs are administered orally. In at least one of the most frequently used drugs, 6-mercaptopurine, adverse reactions based on unexpectedly low leukocyte counts will often be explained by TPMT polymorphism and not by deviations in absorption.
Distribution
For oral as well as parenteral medication several issues related to drug distribution have to be considered; i.e. differences in body composition such as total body water, extracellular water and body fat, and altered binding to various plasma and tissue proteins. Lipid soluble drugs have relatively larger distribution volumes in infants as compared to older children due to the relatively higher amount of fat. But also for water-soluble drugs larger distribution volumes can be noted due to the larger extracellular water component. Inter-individual variation is common. Body composition changes during development. Total water, especially extracellular water, decreases during childhood. In the first months after birth total body fat increases, at later ages a relative decrease occurs. The affinity of plasma protein is different depending on the type of plasma proteins. The most important plasma protein is albumin. Drug binding, both increased as well as decreased, differs for several drugs, due to differences in fetal versus non-fetal albumin characteristics. Not only albumin influences plasma binding. Other plasma constituents do influence drug binding as well. Examples are plasma globulins and glycoproteins, which are generally decreased and free fatty acids which are commonly increased. Higher binding as well as decreased binding was demonstrated for various drugs. No data exist for cytostatic drugs.[11], [26], [27]
Metabolism
Although metabolism occurs in several tissues, the liver is probably the most important site for drug metabolism of cytostatic drugs.
Liver volume and hepatic blood flow determine the amount of drug that can be metabolized. Younger children have a relative high liver volume, and liver volume has a close relation with body surface area and hepatic blood flow.21 Microsomal protein content is about two-third of the maximal concentration, which is reached at an average age of 30years.28 There is an increased intrinsic cytochrome P450 activity, however it is doubtful if that accounts for the increased clearance of most P450 drug substrates in children.29 Phase I and II reactions are still in a process of maturation. In childhood and especially in neonates and infants the expression and activity of both phase I and phase II enzymes differs in many aspects. In this respect, the above mentioned discrepancy in the intestinal wall on expression of m-RNA and activity of CYP3A4 may be present in the liver as well. A point of caution is the interpretation of absolute activity in the body on basis of determination of samples. Although it was shown that liver volume was a parameter correlated with pharmacokinetics.30 Allometric scaling showed that the maximal activity of UGT1A4 was only reached at the age of 18.9years, instead of reaching it at the age of 1.4years. This underscores the importance to take several factors into account.31
Considering the developmental variations in activity of drug metabolizing enzymes there is a major difference in drugs that need a metabolic step prior to getting cytostatic activity versus those drugs, where the parent drug is active as such. In pro-drugs a slower rate of metabolic activation will lead to lower blood levels of the active drug and extension of the period during which the active metabolite is present in the body. On the other hand developmental changes in elimination have consequences as well. If elimination (hepatic or renal) is diminished this will lead to higher blood concentrations and prolongation of the availability of the active metabolite/drug. In case elimination of the prodrug is normal, blood levels of the active drug tend to be lower. However, this might be reversed in case the metabolic step from pro-drug to active metabolite occurs at a slower rate. The final result might be that very low concentrations of active drug are present for a more prolonged interval. Since toxicity and efficacy can be related to either peak concentrations or duration of exposure or both, the effect on toxicity and efficacy cannot fully be deducted from the scheme as depicted in Table 1.
Table 1. (A) Pharmacokinetic alterations related to changes in clearance of compounds formed after activation of prodrugs. (B) Pharmacokinetic alterations relating changes in elimination of intrinsically active drugs.
| Activation | Clearance | ||
|---|---|---|---|
| Decreased | Normal | Increased | |
| A | |||
| Lower enzyme activity | Duration of exposure prolonged Cmax undetermined | Duration of exposure prolonged Cmax decreased | Duration of exposure prolonged Cmax decreased |
| Normal enzyme activity | Duration of exposure prolonged Cmax increased | Duration of exposure normal Cmax normal | Duration of exposure decreased Cmax decreased |
| Increased enzyme activity | Duration of exposure prolonged Cmax increased | Duration of exposure decreased Cmax increased | Duration of exposure decreased Cmax increased |
| B | |||
| Duration of exposure prolonged Cmax increased | Duration of exposure normal Cmax normal | Duration of exposure decreased Cmax decreased | |
Many drugs are substrates for phase I (oxidative) and/or phase II (conjugative) metabolizing enzymes. Variant alleles cause in individuals considerable differences in metabolic capacity. These differences add to the variance caused by developmental changes. In line with this two main classes can be defined. Class I, including amongst others CYP1A1, CYP1A2, CYP2E1 and CYP3A4, which are well conserved and do not have important functional polymorphisms and Class II composed of CYP2B6, CYP2C9, CYP2C19, CYP2D6 which are highly polymorphic.32 Additionally the activity of metabolic enzymes can be different in the various tissues. Since the liver is considered to be the site where most cytostatic drugs are metabolized this report only deals with the ontogeny of hepatic drug metabolic enzymes.[28], [33], [34]
Phase I enzymesCytochrome P450 system
The cytochrome P450 superfamily is a large and diverse group of enzymes divided in 18 families. The function of most CYP enzymes is to catalyze the metabolism (mainly oxidation) of organic substances. About 23 enzymes are relevant for the metabolism of drugs and toxins. It is currently believed that only families 1 through 3 are relevant for metabolism of drugs.28 CYP enzymes catalyze oxidation of many compounds, among them 90% of clinically prescribed drugs.
CYP1A: CYP1A1 is active in adults in the case of pulmonary exposition to polycyclic aromatic hydrocarbons (tobacco smoking). In unexposed individuals CYP1A1 is low or absent.35 The expression during fetal life has been extensively debated, but probably the enzyme is only expressed in the first trimester of fetal life.28 However, CYP1A comes to expression and plays a role in the metabolism of procarbazine, dacarbazine, 5-fluorouracil, etoposide and the SN-38 metabolite of irinotecan.36
CYP1A2: CYP1A2 is a far more important enzyme as compared to the CYP1A1. In fetal liver samples no activity was noted.37 A steady increase in activity and protein levels is noted from birth onwards: in neonates 4–5% of adult levels, in 1–3months old infants 10–15%, in 3–12months old children 20–25%, and in children aged 1–9years at 50–55% of adult levels. Dietary differences influence CYP1A2 expression. In formula-fed children a higher activity was noted as compared to breast-fed infants.[38], [39] CYP1A2 is involved in the inactivation of dacarbazine, procarbazine, temozolamide and to a minor extent etoposide.[32], [40], [41], [42]
CYP1B1: CYP1B1 is mainly an extra-hepatic enzyme.43 Therefore CYP1B1 is probably unimportant in drug metabolism. There is a debate on the expression in fetal liver; since it was only found in 3 out of 6 samples.44 However, these data were not confirmed in a study including 63 fetal liver (22–44weeks gestation) and 12 adult liver samples; m-RNA could not be detected.[28], [43] However, the enzyme is mentioned in relation to the metabolism of docetaxel and mitoxantrone.32
CYP2A/B: The CYP2A family in humans is mainly represented by 3 members. Although CYP2A7 is found, this enzyme and its variants are devoid of any activity.45 CYP2A6 is found in adult liver tissue.46 In fetal samples in only one out of six samples CYP2A6 was detected.47 Crespi et al. found the enzyme in a single sample originating from a child with a postnatal age of 17weeks.48 Therefore, it can be concluded that development of activity of the enzyme starts somewhere in the first year of life. In cytostatic treatment CYP2A6 is a major enzyme in 5-fluorouracil metabolism and enhances the activation of the prodrug tegafur.49 As a consequence, if ever 5-fluorouracil treatment in infants is indicated, this orally taken prodrug is not a good choice. CYP2A6 is involved in activation of cyclophosphamide into hydroxycyclophosphamide. Since it is not the major enzyme active in this pathway the effect of absent or decreased activity will be limited.50
For CYP2B6 only recently data on ontogeny became available. The hepatic specimens originated from 217 patients (age range 10weeks gestational age to 17years, median age 1.9months). Overall, CYP2B6 expression was detected in 75% of samples. However, the percentage of samples with detectable CYP2B6 protein increased with age from 64% in fetal samples to 95% in samples from donors >10years of age. There was a significant, but only 2-fold, increase in median CYP2B6 expression after the neonatal period (birth to 30days postnatal) although protein levels varied 25-fold in both age groups. The median CYP2B6 level in samples over 30 postnatal days to 17years of age (1.3pmol/mg microsomal protein) was lower than previously reported for adult levels (2.2–22pmol/mg microsomal protein. The authors showed that there was no correlation between CYP2B6 levels and CYP3A4, CYP3A5.1 or CYP3A7 activity.51
CYP2B6 is involved, as a major pathway, in the activation of cyclophosphamide and ifosfamide. There is a close correlation between CYP2B6 expression and activation of cyclophosphamide into its hydroxy-metabolites. However, there are clear differences between ifosfamide and cyclophoshamide. Probably it is the most active pathway for cyclophosphamide.52 The activation trough 4-hydroxylation for ifosfamide is to a large extent under control of CYP3A4.53 Thiotepa undergoes desulfuration to an active derivate with a long t½ by means of CYP2B6 and CYP3A4.54 Activation of procarbazine is mediated by CYP2B6 as well.36 In adults there are important racial differences. CYP2B6 1459C>T polymorphism is noted in 13% of the Caucasian population and has shown to have a lower activity as compared to other variants. Whether the differences related to CYP2B6 in gender, i.e. Caucasian females have a lower expression, is relevant for children is yet unknown.55
CYP2C: In respect to the use of cytostatic treatment CYP2C9, CYP2C18 and CYP2C19 are important. Data on CYP2C members are often not differentiating between the various members of this CYP family, whereas data on CYP2C18 are nearly absent.28 It was shown that in early fetal samples CYP2C is as low as 1% of adult value. In the last trimester of pregnancy fetal liver concentrations increase to 10%. These values increase from 25% of adult activity level at the age of 5months to 50% at the age of 10years.[56], [57] The data on CYP2C9 and CYP2C19 are often not differentiated from each other, but there are data that indicate that fetal expression of CYP2C19 is found from 12weeks onwards, i.e. 10–20% of adult values. From birth onwards there is an increase during 5months to 50–75% of adult values. Up to 10years of age CYP2C19 expression is highly variable. From puberty onwards normal adult values are reached.58 However, PK data on phenytoin and warfarin could not be explained by findings related to the ontogeny of CYP2C19.[59], [60]
All CYP2 enzymes, but especially CYP2C19, are involved in the activation of both cyclophosphamide and ifosfamide.[53], [61], [62] Since CYP2B6 is the most important enzyme for this step, the relevance of other CYP2Cs will be quite limited provided that the activity of CYP2B6 is not severely decreased in infancy. CYP 2C9 is to a limited extent involved in the activation of tegafur and metabolism of idarubicin.[32], [49] As a consequence the low expression of the CYP2C family will not have a major impact on the pharmacokinetics during infancy. Eighty-five percent of inactivation of paclitaxel is induced by CYP2C8.63 However data on expression of this enzyme in infancy are lacking
CYP2D6/8: CYP2D6 is involved in many oxidative processes. In 5–10% of the Caucasian population CYP2D6 activity is deficient.40 In fetal samples activity, as measured by Treluyer et al., showed an increase with advancing gestational age. Postnatal data on newborns from 7 to 28days showed mean protein levels of 30% of adult levels. Up to the age of 5years there was an increment up to 70%.64 Only in adults, in contrast to children, a correlation of CYP2D6 protein and mRNA was detected. It was shown that there are many transcripts resulting in inactive splice variants. Based on the discrepancies of protein content and m-RNA expression in children it is suggested that at younger age more variants appear. This indicates that the findings of Treluyer et al. do reflect expression of CYP2D6 m-RNA, but merely reflect activity.[65], [66]
In relation to cancer treatment in childhood, CYP2D6 might in the future be important, since it is involved, as CYP3A4 is, in the metabolism of the EGFR-inhibitor gefitinib (Iressa®). CYP2D7 is a variant carrying only a single insertion at position 137 in exon 1, which causes premature termination. Functional activity of CYP2D7 is not assumed.
CYP2E1: CYP2E1 is involved in metabolic pathways of several therapeutics, including acetaminophen and halothane. The enzyme also has an important role in the bioactivation of many small molecular weight toxins, including ethanol, benzene, toluene, N-nitrosodimethylamine, and halogenated alkanes.28 However the relevance for cytostatic drug metabolism is limited. There is no correlation of fetal m-RNA expression and activity. RNA transcripts show modest differences between fetal samples from the third trimester and samples up to 28days after birth. From 1month until 1year transcript levels increase to 50% of adult levels.[67], [68] Enzyme protein levels augment from birth onwards to adult levels, which are reached at 90days postpartum.69 CYP2E1 is one of the inactivating enzymes in dacarbazine metabolism.
CYP3A family: The CYP3A4 family is involved in the metabolism of about 50% of the drugs currently marketed.70 CYP3A4 is the most important member of the CYP3A family, but the enzyme is prone to wide inter-individual variation, mainly due to genetic factors.[57], [71]
In fetal life the most predominant CYP3A is CYP3A7. CYP3A7 is about 20-fold higher and decreases to adult levels at the age of 1year. Generally speaking CYP3A7 remains the dominant enzyme up to the age of 1year.[28], [72] CYP3A4 and CYP3A5 are low expressed.[73], [74], [75], [76] At the age of 1month 30–60% of adult values of CYP3A4 are reached. Lower CYP3A4 levels are noted during childhood, especially in the younger age groups.[28], [72] During infancy, CYP3A4 activity can during some periods even be slightly higher as compared to adults. Later on lower activity is found and only after the age of 10years mean adult levels are reached.77 CYP3A5 in the liver exceeds CYP3A4 in African Americans, but due to genetic polymorphism it is only expressed in one third of Caucasians.[78], [79] The contribution of CYP3A4 and CYP3A5 can often not be discerned due to the large overlap in substrate specificity. CYP3A5 comes to expression during infancy.[68], [80]
CYP3A4 is the major enzyme in the metabolism of many cytostatic drugs. There are no indications that CYP3A7 is an important player in the metabolism of cytostatic drugs in adults, which might be related to the low expression. Ifosfamide and cyclophosphamide are to a large extent activated by CYP3A4/5, but are also involved in the formation of inactive dechloromethyl- metabolites, which are responsible for neurotoxicity. Inactivation by CYP3A4/5 is noted for vinca-alkaloids, docetaxel, etoposide, irinotecan, taxol, teniposide, paclitaxel, busulfan, cisplatin, doxorubicine, topotecan, mitoxantrone, thioTEPA, imatinib, gefinitib. ThioTEPA undergoes desulfuration to an active derivate with a longer t½ by means of CYP2B6 and CYP3A4.54 Within similar drug groups variations related to metabolic pathways exist. For instance docetaxel is metabolized for 60–90% by CYP3A4/5, whereas CYP2C contributes for 85% in the metabolism of paclitaxel.81 It is unclear whether in infancy for a specific drug the contribution of each pathway is similar. Whether in infancy racial differences additionally influence the extent of use of the various pathways needs still to be investigated. For instance clearance related to CYP4A5 of etoposide was lower in people of African descent versus Caucasians.82 If this is also the case in infants is unclear.
Flavin-containing monooxygenase system (FMO)
In man only FMO1, 2 and 3 are active in drug metabolism.83 In liver there is a transition from fetal into adult expression. Initially FMO1 is the most predominant enzyme; later on FMO3 is most abundant. FMO1 is suppressed within 72h after birth. Expression is detected only after 1month and before the age of 10months. Intermediate expression is noted up to the age of 11years.84 In adults FMOs don’t play a relevant role in metabolism of cytostatic drugs. There are no data that in infants this would be the case.
Alcohol dehydrogenase
Alcohol dehydrogenase is encoded by seven genes. There is progressive expression of ADH of all three class 1 enzymes during human development.85 In early fetal life only ADH1A has been detected in the liver using starch gel electrophoresis. Later on ADH1B and ADH1C appear. In preterm infants, ADH1B is the most expressed enzyme. In adults ADH1A is low or absent, ADH1B and ADH1C are equally expressed.[85], [86] However, there is uncertainty on fetal expression of ADH1A, since m-RNA (as determined by Northern blotting) showed no expression of one of the two liver samples of unspecified fetal age.87 The relevance for cytostatic treatment in infants is limited. ADH only plays a role in detoxification of aldophosphamide into alcophosphamide. Other pathways in aldophosphamide metabolisms are ALDH and GST, whereas the pathway leading to the most important active compound, phosphoramide mustard is not influenced by ADH.
Aldehyde dehydrogenase
Aldehyde dehydrogenase enzymes are a group of enzymes catalyzing the oxidation of aldehydes to carboxylic acids. In mice there is decreased expression of all enzymes of this family in fetal as well as in the early postnatal period.88 In man there are no data on the ontogeny of these enzymes. The enzymes play a role in detoxification of cyclophosphamide; i.e. the conversion of aldophosphamide into carboxy-phosphamide. For tumors, resistant for cyclophosphamide increased levels of aldehyde dehydrogenase activity were found.89 If the ontogeny in humans is similar to mice, increments of the active compounds of cyclophosphamide are likely.
Aldehyde oxidase (AOX)
Aldehyde oxidase is to a minor extent involved in the metabolism of 6-mercaptopurine and methotrexate. Although the activity in fetal liver was found to be 30% of the adult value, in neonatal erythrocytes the activity was found to be 50% higher than in adults.[90], [91] In Japanese neonates activity was 10–15% of the activity in adults, as measured by urinary excretion of the relevant oxidation product. At the age of 1year there was a linear increase to adult values.92 For cytostatic treatment in infants the decreased activity of the enzyme is of limited importance for methotrexate as well as 6-mercaptopurine. The major pathway for methotrexate is renal excretion. For 6-mercaptopurine thiopurinemethyltransferase (TPMT) is the major enzyme in the metabolic decay of the drug.
Glutathione S-transferase (GST)
GST forms a family of enzymes from 16 genes and six subfamilies.93 There is a great overlap for substrate.94 Pacifi and Rane showed for styrene oxide that there was a nearly threefold decreased activity in fetal tissue as compared with adult liver tissue.95 During ontogeny there are shifts in respect to the various enzymes. For GSTA2 an increase is noted after birth during the first 2years of life. Also GSTA1 shows an increase and, as compared to GSTA2, there is a somewhat higher liver protein content during the first 1.5years of life. For GSTP a decrease from fetal values to nearly no expression is seen. GSTM has a low expression in fetal liver, but in neonates it shows a nearly similar expression as compared to adults.96 GST is involved in the formation of 4-glutathionyl-cyclophosphamide from aldophosphamide. Considering the data of Pacifi en Rane, increased levels of the active metabolites of cyclophosphamide are to be expected. GST also plays a role in the metabolism of busulfan and chlorambucil, which may explain increased toxicity due to delayed elimination.
Sulfotransferase (SULT)
Sulfonyltransferases are categorized in four families. Limited data exist on the various subtypes. For the SULT 1A family a decrease in expression, increasing 3-fold to levels in the adult age, were described.97 There is a difference in the expression of subtypes in relation to ontogeny. SULT1A1 is in the fetal, neonatal and adult period present at the same level.98 SULT1A3 protein is decreased postnatally (10-fold).[99], [100], [101] SULT1E1 decreases during fetal life and infancy to adult low levels.98 For SULT2A1 a steady increase from low fetal levels to adult levels was found.98 For the other SULT enzymes limited data are available. SULT enzymes are in adults not involved extensively in metabolism of cytostatic drugs, and there are no data in infants.
UDP glucuronyl transferase (UGT)
UGT enzymes catalyze the conjugation of hydrophobic compounds to form β-d-glucopyranosiduronic acids, which are excreted renally and in the bile.102 Two families exist, i.e. UGT1 and UGT2, and in total 16 functional genes are known. UGT1A1, responsible for bilirubin glucuronidation, is nearly undetectable in fetal liver. Enzyme expression increases independent of gestational age immediately after birth, and reaches normal adult values after 3–6months. UGT1A3 level is at birth about 30% of adult value.103 UGT1A6 is in fetal liver 1–10% of adult levels. Following birth there is a slow increase in expression and at the age of 6months 50% of adult levels are expressed; its activity is only complete after puberty. For UGT2B7 there is an increase after birth from 10% to 20% to adult levels, reached at the age of 2–3months.104 Analysis of 13 UGT enzymes according to three age cohorts, i.e. 6–12months, 13–18months and 19–24months revealed no differences for UGT1A1 and UGT2B7 transcripts, as compared to adult samples. For UGT1A9 there was a progressive increase with age, whereas UGT2B4 was constantly low at a level of 35% of adult values. For both enzymes regulation of expression extends beyond 2years of age.105 A progressive increase in UGT2B7 activity across five age groups,<1year of age, 1–5years of age, 6–11years of age, 12–17years of age, and adults has been noted in another study. However, after allometric scaling using the 3/4 power rule normal values were predicted at the age of 2–3months.106
UGT enzymes are involved in metabolism of anthracyclines, topotecan and irinotecan. In addition to the age related variability in activity of UTP1A1 there are differences in activity related to the polymorphic expression of this enzyme. It was shown that the UGT2A1∗28 allele was related to a lower rate of conjugation of SN-38, an active metabolite of irinotecan, resulting in excess toxicity.107 The camptothecans are metabolized through UGT1A9. As a result progressive improvement of clearance is to be expected during several years following birth.
N-acetyltransferase (NAT) and epoxihydrolase
Knowledge on NAT ontogeny is limited. NAT1 is lower in fetal samples as compared to adults.108 Epoxihydrolase (EPHX 1 and 2) enzymes are decreased at birth.34 These enzymes and NAT enzymes are not linked to major pathways in the metabolism of cytostatic drugs.
Renal excretion
Renal function in early infancy is severely diminished. In the first weeks to months of postnatal life, renal vascular resistance decreases and blood flow increases. Early after birth blood pressure rises and induces a substantial increase in renal function. This is relevant for both glomerular filtration and tubular secretion during the first year of life.109 However, glomerular filtration reaches normal values only from the age of 1year onwards.110 Tubular drug elimination (transport and metabolic processes) is probably related to tubular immaturity of the kidney. It is assumed that normal tubular function is fully developed by the age of 7months.111 There are no data on development of tubular function specific for the elimination of cytostatic drugs.
Other general factors in infant cytostatic treatment
Many factors involved in expression or activation of enzymes are only very partially known. In anti-cancer treatment, also in infants, the effect of co-administered drugs (among them dexamethasone and ketoconazole) are only partially known.112 This may be very prominent in pediatric oncology patients who are treated with several drugs during a prolonged period. An additional factor of consideration in these patients is also forced diuresis during administration of cytostatic drugs.113
Cytostatic drugs need to be divided in prodrugs and drugs where the parent compound has cytostatic activity on its own. In case enzymes are non- or low-expressed at birth a prolonged presence of the parent drug can be seen,[2], [113], [114] whereas for prodrugs this might lead to decreased serum levels of the active compounds and but there will also be a longer formation of active metabolites. However, also the decreased detoxification by the same enzymes or enzymes in the same group might interact with the drug concentration. The final results might be that the drug levels can be relatively high and additionally the time of exposure can be longer. Considering the changes in metabolic rate of enzymes, as based on ontogeny, the scheme in Table 1 can be designed.
In this review this is only presented in detail for cyclophosphamide. Concerning cyclophosphamide, the enzymes CYP2A6, 2B6, 3A4/5, 2B6, 2C9 2C18 and 2C19 are involved in the metabolic step to 4-hydrocyclophosphamide. But CYP3A4 is also involved in the formation of chloroacetaldehyde. The low CYP3A4 levels might result in lower levels of chloroacetaldehyde and less 4-hydroxycyclophospamide, both resulting in less activity of the drug and less toxicity related to the dechloromethyl-metabolite.[115], [116], [117] CYP 3A4 levels can exceed adult activity at certain time periods during infancy. As a result the balance of efficacy and toxicity is subjected to substantial shifts.77 The relatively high levels early after birth of CYP2B6 might promote cytostatic activity. And in the very first weeks after birth the decreased glutathione-S-transferase activity might be causative for delayed detoxification of phosphoramide mustard.[21], [32], [40], [118] This all illustrates that PK equipoise can vary substantially in the early years of life, and can result in other risk versus efficacy ratios.
Another point in drug metabolism is the polymorphic expression of enzymes involved in the different biotransformation pathways.119 Polymorphism might result in decreased activity of the involved enzyme. Several enzymes involved show hardly any polymorphism; e.g. CYP3A4. Other enzymes, such as CYP2A6, 2D6, 2C9 and 2C19, are highly polymorphic.32 In adults it has been shown that polymorphisms can lead to PK alterations and as a result in altered pharmacodynamic activity.[120], [121] The effect on moment of expression and activation in relation to ontogeny for the various subtypes is unknown.
A yet unknown factor in infant chemotherapy is the ontogeny of drug transporters. In mice there is a limited expression of P-glycoprotein (P-gp) in the intestine at birth, however, levels of P-gp in kidney and liver showed adult values.122 In rat the amount of expression of Multidrug Resistance Protein 2 (MRP2) is at birth approximately 70% of adult values. After birth the expression of MRP2 exceeds adult expression after 25–45days. In the female rat higher MRP2 levels were found to peak at a later age.123 Studies on m-RNA expression of MDR1, MDR2, and MDR3 in BALB/c and C57BL/6 mice showed high variability among strains, among different organs and among age groups. An additional finding was that the expression of various isoforms increased at older ages.124 Data on ontogeny of drug transporters in man are very scarce.[23], [24] In respect to absorption limited data exist for CYP3A4 and 1A1, which are lower expressed in the intestine at an younger age. This may result in an increased absorption at a younger age.[23], [25] In the study of Stahlberg, other detoxification enzymes have normal activity in normal intestine of pediatric patients. But in this study the number of patients with normal villi at the age of 1year (n=8) was too low to make any conclusive statements for this specific age range.23 Data on developmental aspects of drug transporter enzymes within the body and on those active in renal excretion nearly non-existing.
The differences in pharmacodynamics (PD) have been touched upon earlier by mentioning the altered binding to target proteins and aspecific binding to tissue protein. Also differences of expression of metabolic enzymes in the tumor cells themselves will influence the effect of the drugs.[125], [126] As such overexpression of CYP1B1 was related to docetaxel insensitivity.127 To date hardly any study on pediatric malignancies focus on expression of drug metabolizing enzymes. Altered PD can especially be caused by aspecific binding or to differences in expression and avidity of membrane receptors. Another obstacle is the intracellular handling of drugs in relation to the differences in disease characteristics per age.
In this review data on cytostatic therapy in children of less than 2years of age are summarized, with a focus on data on children <1year. Studies were primarily selected if patients <1year were reported. If these patients were not available or only limited reports were found, studies on patients up to the age of 2years were included as well.
Alkylating agents
Cyclophosphamide
After oral absorption bioavailability of cyclophosphamide in adults is dependent on the dosage used indicating a lower absorption with a higher dosage.128 With low doses (1–2mg/kg) there is nearly complete absorption of the drug.129 After oral administration (3–6mg/kg) the bioavailability is reported to vary between 34% and 97%.128 Cyclophosphamide itself is an inactive drug and its metabolism results in an array of active substances. Cyclophosphamide is oxidized by several CYP450 enzymes into 4-hydroxy-cyclophosphamide. 4-Hydroxy-cyclophosphamide diffuses in the cell, but is not cytotoxic itself (Fig. 1). There is a direct equilibrium of this compound with aldophosphamide. After β-elimination of acrolein, phosphoramide mustard arises. The acrolein metabolite is considered to be the product responsible for urotoxicity. Several isoenzymes are involved in the metabolism, including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19.50 CYP2B6 has the highest activity for the activation into 4-hydroxycyclophosphamide. In adults CYP3A4 is responsible for 10% and CYP2C19 for 10% of its activation.53 Since phosphoramide mustard from the plasma does not enter the cells, 4-hydroxy-cyclophospamide levels are suggested to reflect the biological activity of cyclophosphamide. In erythocytes higher concentrations of 4-hydroxy-cyclophosphamide than in plasma are found. Also activation by CYP450 enzymes within the malignant cell has been suggested. Additional activity is presumed to be related to acrolein. It possibly enhances tumor cell kill by glutathione depletion.[50], [130], [131] An alternate pathway leading to depletion of glutathione is the formation of chloroacetaldehyde (with intrinsic cytostatic activity) via 2- and 3-dechloroethylcyclophospamide directly from the parent compound cyclophosphamide. This step is under control of CYP3A4.[132], [133] Aldophosphamide can be detoxified into carboxyphosphamide.134 Cyclophosphamide resistant tumors can express at a higher level aldehyde dehydrogenase enzymes, which are involved in this pathway. Activity of these enzymes can however be inhibited by acrolein.135 Other processes involved in cyclophosphamide metabolism are e.g. conjugation with glutathione, aldose reduction and alcohol dehydrogenation. In adults a very substantial amount (up to 80%) of cyclophosphamide is metabolized to carboxy- and ketophosphamide. Therefore only the aldophosphamide products escaping these oxidation steps can eliminate the acrolein group to form the active phosporamide-mustard136 Elimination of the various compounds is performed by the kidneys. The parent drug and its metabolites are excreted in the urine. However, only 15% of the parent drug is renally excreted. A high intra- and inter-patient variability in PK has been reported with serum half life values (t½) of 8.21±2.25h.128 At higher doses kinetics are saturated resulting in prolonged half-lives.[21], [24], [115] The half-life for several of the metabolites are often shorter.50 Cyclophosphamide is a potent enzyme inducer resulting in an increased clearance after infusion on successive days.[18], [19] On the other hand, renal insufficiency results in a lower clearance of the drug.137
Fig. 1.
Metabolism of cyclophosphamide. The enzymes with highest activity are depicted in bold.
No data for oral administration in infants are available. Cyclophosphamide is in children, including infants, usually administered by intravenous route. From the data based on ontogeny of metabolic enzymes and the data from literature the following effects in infants can be expected. Very young infants probably will have a reduced production of dechloroethylcyclophosphamide, based on the reduced CYP3A4 activity. This might result in more substrate for the formation of the more active compounds and less neurotoxicity, but increased urotoxicity. However the potential formation of hydroxycyclophosphamide is regulated by CYP2A6, which shows decreased activity as well. In respect to the aldophosphamide decay, one of the major metabolic pathways, the formation of carboxycyclophosphamide is decreased in infancy. This will result in more substrate for the formation of phosphoramide mustard, increasing cytostatic efficacy, and acrolein toxicity. After a few months the activity of CYP3A4 can surpass the adults levels, resulting in more dechloroethylcyclophosphamide what might lead to less cytostatic activity but increased neurotoxicity.
To date there are limited data on age-related differences in concentrations of metabolites related to enzyme activity and cyclophosphamide metabolism. There are also no data on CYP450 activity in pediatric tumor cells or intra-tumor phosphoramide mustard concentration. In children elimination half-life is substantially lower, but inter- and intra-individual variability is high.138 Mean t½ values of 1.48–4.86h were reported in children ranging in age from 0 to 18years.[115], [116], [117], [139], [140] A direct correlation was found for dosage versus t½, although parameters such a volume of distribution and clearance were not correlated with t½.115 Use of dexamethasone in children resulted in a shorter t½, which is in contrast to the use of prednisone which caused a more prolonged clearance.115 Co-administration of azoles is related to prolonged t½ values due to inhibition of CYP3A4/5.[50], [115] In a report by Yule et al. 5 children were below the age of 1year (range: 0.17–0.83years) and 2 children were between 1 and 2years of age. In this study t½, volume of distribution and clearance were not substantially different.115 No significant differences were reported for the AUC of cyclophosphamide and its inactive metabolites dechloroethylcyclophosphamide and 4-ketocyclophosphamide, but a high inter-patient variation was found for cyclophosphamide as well as it metabolites.116 Yule et al. described in 36 children, ages ranging from 2 to 16years with non-Hodgkin’s lymphoma, a correlation between a prolonged t½, indicative of poor metabolism and activation of cyclophosphamide, and higher levels of the inactive compounds carboxyphosphamide and dechloroethylcyclophosphamide.117 In several other reports only a very limited number of patients between the ages of 0 and 2years were described. Differences in t½ and clearances of cyclophosphamide were not reported. With respect to cyclophoshamide metabolism McCune et al. provided data on cyclophosphamide, 4-hydroxy-cyclophosphamide and carboxyethylphosphoramide mustard (a non-toxic metabolite of aldophosphamide) in neuroblastoma patients (ages 1.30–9.37years).141
For infants the following assumptions can be made: due to the very limited renal function and enzyme immaturity in the first months of life substantial reductions are necessary. In addition activation of metabolites might be strongly reduced as well as decreased neurotoxicity might be predicted based on decreased CYP3A4 activity.
Ifosfamide
Ifosfamide has many similarities with cyclophosphamide. The structure of the molecule differs mainly in the position of the chloroethyl moieties. The drug is metabolized in a similar way as cyclophosphamide, but for certain steps the rate of metabolism is quite different. As a result, a higher dechloroethylation rate is noted resulting in increased neurotoxicity. Both parent drug and metabolites are excreted renally, and due to the slower rate of activation the amount of unaltered parent compound in the urine can be as high as 50%.142 Ifosfamide is metabolized to dechloroethyl-ifosfamide, which is further degradated into chloroacetaldehyde, with its neurotoxic effect.143 The metabolic pathway goes from 4-hydroxy-ifosfamide to aldoifosfamide into isofosforamide mustard, which is in fact the cytotoxic compound similar to phosphoramide. Ifosfamide has a longer half-life as compared to cyclophosphamide, i.e. in adults 15h in case of dosages of 3.8–5.0g/m2. At lower doses of 1.6–2.4g/m2 the half-life is however the same as for cyclophosphamide.[41], [42], [43], [144] Similar alkylating activity is found at substantial higher dosages as compared to cyclophosphamide; 3.8 versus 1.1g/m2.142 At lower dosages less inactive dechloroethyl-compounds are produced.145 In its metabolism distinctive differences exist in the regulation by the various CYP450 enzymes as is also seen in the metabolism of cyclophosphamide.146 CYP3A4 and CYP2B6 are the major enzymes involved in the metabolism of ifosfamide; both at the beginning of the metabolic pathway for dechloroethylation as well as the formation of aldoifosfamide. In contrast to cyclophosphamide the formation of the inactive dechloroethyl metabolite (under control of CYP3A4 and CYP2B6) is substantially higher (up to 50%).145 In addition about 25% is excreted unchanged in the urine.[41], [147] In contrast to phosphoramide there is discussion whether extracellular ifosforamide mustard is capable to enter the cell and elicit cytotoxic effects.148 Active compounds are in children able to pass the blood–brain barrier, even in higher concentrations as cyclophosphamide metabolites.
Similar to cyclophosphamide an increment in clearance rate is observed after several days of infusion.149 In a pediatric study of 5 cases differences with respect to enantiomers were found, i.e. mean t½ was 3.0h for S-ifosfamide versus 4.5h for R-ifosfamide. No differential effect on auto-induction was noted for the enantiomers. Although S-ifosfamide has a greater efficacy, a greater toxicity and a higher therapeutic index when tested in five in vitro tumor models, the clinical relevance of these findings in PK differences in children is not yet clear.[150], [151] Higher response rates in adults were noted after bolus infusion as compared to continuous infusion.152
Half-life in children is dependent on dosage. In children from 7 to 16years t½ values ranges from 1.5 to 5.3h using doses ranging from 1 to 4g/m2.147 In children bolus infusion resulted in a reduced production of dechloroethylated metabolites.153 In an Italian study 1-h infusions resulted in more urological problems, whereas patients on 24-h infusions had more neurotoxicity. This might be explained by the saturation of CYP3A4 activity in respect to the formation of the dechloretylated metabolite. The urological problems reflect higher amounts of acrolein in infusions of short duration. The resulting higher amounts of ifosforamide also explain the higher response rate after bolus infusion in adults. Short duration of infusion indeed proved to result in higher production of the cytostatic ifosforamide mustard and the bladder toxin acrolein, whereas prolonged transfusion results in the formation of the non-cytostatic, but toxic 2- and 3-dechloroethyl-ifosfamide.153 Also administration at consecutive days resulted in lower concentrations of the parent drug but higher dechloroethylated metabolites, increased clearance and shorter half-lives. All phenomena are indicative for auto-induction. This auto-induction is presumed to occur very quickly, i.e. after 2days it is apparent.153 Boddy et al. compared bolus versus continuous infusion in 17 children; 4 of them were below the age of 2years. A boy of 0.8years was the only one younger than 1year. Once again, it was shown that there was up to 70% less of dechloroethylated metabolites in plasma following bolus administration compared to continuous infusion. No age specific PK data were given.149 In another report of 16 children PK of the parent drug, the carboxylated and the dechloroethylated metabolites were investigated. Only 3 were below the age of 2years (1, 1, and 1.9year); no difference with the older children became apparent.154
Based on the lack of data in infants it is hard to make conclusive statements on the correct posology in infants. Very young infants may experience increased cytotoxicity due to the lower activity of CYP3A4 and the resulting lower levels of dechloroethyl-ifosfamide. Also the limited clearance by renal excretion and lower ALDH may increase cytotoxicity. Whether less neurotoxicity during infusions of limited duration is seen in infants versus older children is doubtful. At an older age the activity of CYP3A4 is higher and neurotoxicity may increase.
Mainly due to the limited renal function substantial dose reductions are advised in young infants.
Procarbazine, dacarbazine, temozolamide
Classical alkylating agents have a chloroethylgroup. In contrast, drugs like procarbazine, dacarbazine (DTIC) and temozolamide do not have such a group.
Procarbazine is a weak toxic prodrug. It is fully absorbed after oral administration. The drug is readily distributed over the body and equilibration of plasma and cerebrospinal fluid is reached within 15min. Renal excretion is ⩾75% in 24h.155 Potential pathways of activation are chemical decomposition and oxidation in the liver. The most probable way the drug exerts activity is the production of methyl- or benzylazoxy-intermediates which decompose into diazonium ions. However there is accumulating evidence that production of O6-methylguanine is a very potent mode of activity.156 Major steps in metabolism are under control of CYP450 enzymes (1A and 2B) and MAO.41 Since the use of procarbazine in infants is extremely low, there are no data for this age group. In infants dose reductions are to be advised based on the limited renal function and slower metabolic pathways.
Dacarbazine (DTIC) has been developed as a purine anti-metabolite. There is high variability in absorption of the drug. This is in humans a limiting step in the activation pathway. In contrast to procarbazine, there is poor CSF penetration. The drug is excreted in the urine, about 50% in unchanged form, and 20% as metabolites. There is minor hepatic clearance.155 The action of the drug is however not via this pathway but by formation of monomethyltriazine-imidazole-carboxamide (MTIC), but also by generation of O6-methylguanine.157 The last step is formation of the inactive metabolite 5-aminoimidazole-4-carboxamide (AIC). Enzymes involved in the metabolic process are CYP1A1, 1A2 and 2E1.41 There is a consensus how to relate the dosage to the glomerular filtration rate. Similar to procarbazine there are no specific data for infants available.
In infants dose reductions are to be advised based on the limited renal function and slower metabolic pathways.
Temozolamide is another imidazotetrainone. In humans the formation of MTIC from dacarbazine is a limiting step for activation. Temozolamide overcomes this problem by spontaneous decomposition under physiological circumstances into MTIC. This spontaneous decomposition is pH dependent. Increased turnover is noted at a pH of 7.0. As a result decomposition may occur in the gastro-intestinal tract in case acid production is limited, either mediated by co-medication or due to age related low acid-production.14 After a further down step O6-methylguanine is formed. The last step is formation of the inactive metabolite 5-aminoimidazole-4-carboxamide (AIC). The drug is renally cleared.
In a study on 39 children with various tumors (median age 7.2years, range 0.7–21.9years) increase of body surface area and age were linked with an increase clearance of the drug.158 An Italian trial comparing adults and children confirmed this finding.60 Based on 16 patients (median age 11years, range 1–19years) with acute lymphocytic and non-lymphocytic leukemia it was concluded that pharmacokinetic parameters were similar to those found in adults. However, there was a discrepancy between refractory and relapse patients, i.e. the O6-methylguanine-DNA methyltransferase (MGMT) was increased in the latter group. This might be indicative for temozolamide resistance in these cases. Also in a report on pediatric solid tumors low or absent MGMT activity was related to the occurrence of a response. However there are also reports contradicting this observation.[147], [159] No specific data for infants are reported to date. For this group the following assumptions can be made. Due to the spontaneous degradation of temozolamide, dose reduction may be needed since accumulation of MTIC may occur due to rate limiting steps later on.
In infants dose reductions are to be advised based on the limited renal function and slower metabolic pathways. The lack of data for procarbazine, dacarbazine and temozolamide in infants illustrate once again that there is a need to collect PK data in as much children as possible. This is especially the case for the currently in brain tumors very frequently used temozolamide.
ThioTEPA
The cytostatic effect of TEPA is the induction of DNA lesions. Two major pathways of action of thioTEPA itself are probable. One pathway results in the binding of two DNA strands to the molecule. More important seems to be the formation of aziridine, which crosslinks with DNA. After infusion the drug is in part metabolized into TEPA in a CYP450 catalyzed reaction. ThioTEPA is metabolized by the same CYP enzymes (2B1, 2C11, 3A) as cyclophosphamide. Due to inhibition of CYP3A4 by thioTEPA, metabolism of co-administered cyclophosphamide is altered.[32], [160] The role of other metabolites with alkylating potential such as non-chloroTEPA and TEPA-mercapturate is still not fully clarified.161 If given orally there is a very rapid absorption. The mechanism of action of thioTEPA is not fully clarified. The drug is excreted renally.162
ThioTEPA is in childhood only used as intravenous solution. In children >2years of age undergoing bone marrow transplantation with a conditioning regimen including thioTEPA PK data were not different from the those in adults.163 In childhood dose-dependent PK were observed. Higher dosages of thioTEPA resulted in a decline of plasma clearance and the increased formation of TEPA seemed to be limited. TEPA had a longer half-life (4.3–5.6h) than thioTEPA, which has biphasic half-lives of 0.14–0.32 and 1.34–2.0h. ThioTEPA is often used to treat brain tumors. Levels in blood and cerebrospinal fluid are nearly equal for both thioTEPA and TEPA.66 Although thioTEPA is used in young children with brain tumors, no specific data for the age range <2years could be recovered from literature. By extrapolating the data on ontogeny of metabolism one might conclude that in very young infants a prolonged exposure of the active TEPA, due to low renal function, can be presumed. Since both thioTEPA and TEPA are active compounds the decreased conversion to TEPA, might not be relevant for posology.
Lomustine (CCNU) and carmustine (BCNU)
Both lomustine (CCNU) and carmustine (BCNU) belong to the nitrosurea group. Their activity is largely dependent on the presence of a chloroethyl moiety, which decomposes to chloretylcarbonium. After splitting of the Cl-atom a binding with DNA is established. DNA cross-linking occurs later on.[164], [165] Metabolism, including activation, is dependent on rather unspecified CYP450 enzymes.[166], [167] The agents are rapidly absorbed and are lipophilic, the volume of distribution is linked to body fat and serum fat content and the drug is renally excreted. No data in infants were found. Related to the CYP450 dependency, a prolonged activity might be possible in infants. In theory they run the risk that after saturation of the normal pathway a higher concentration of toxic alkylated metabolites might occur.[167], [168], [169] In infants dose reductions are to be advised based on renal excretion, higher serum values can be predicted due to low body fat and slow rate of metabolism.
Chlorambucil
Activity of chlorambucil is similar to ifosfamide and cyclophosphamide based on the presence of an azidinium ring resulting in alkylation and crosslinking of DNA, RNA and proteins.170 After oral administration peak levels of chlorambucil are reached within 1h. The drug is metabolized in the liver and after administration of radio-labeled chlorambucil over 50% of radioactivity is found in the urine. In contrast to ifosfamide and cyclophosphamide metabolism into active compounds is not needed per se; although after oxidation di-2-chloroethyl-2 (4-aminofenyl) acetic-acid-mustard is an active metabolite. For the decay glutathione (GSH) and glutathione S-transferase (GST) activity are reported.41 No data on infants were recovered from literature. As a result activity of the drug after allometric scaling in infants might result in increased toxicity due to prolonged excretion of the drug and metabolite.
Busulfan
Busulfan belongs to the groups of alkyl–alkane sulfonates. These react through binding to thiol groups of amino acids and binding to guanosine. The cross linking of DNA capacity is, however, questioned. Busulfan has a high variable bioavailability. The drug has a high penetration in the brain due to its lipophilic characteristics. The drug is metabolized by glutathione conjugation followed by oxidation.40 The role of glutathione-S-transferase polymorphism with respect to busulfan conjugation is still debated.171 In the urine 3-hydroxysulfolane, tetrahydrothiofeen-1-oxyde and sulfolane are recovered in the urine. Busulfan itself is nearly undetectable in the urine.
The therapeutic index in children undergoing hematological stem cell transplantation is however narrow. It was demonstrated that an AUC of 78mgh/l resulted in optimal event-free survival rates. In case a high AUC is reached the risk for graft-versus-host disease increases.172 Lower Cmax values were related to a higher risk for sinusoidal obstruction syndrome (formerly called veno-occlusive disease) of the liver.173 Inter- and intra-patient variance of blood concentration is significant.[174], [175] It has been shown that in busulfan the half-life elimination decreases substantially; from 3.4h after the first dose to 2.3h. A major difference in t½ in subsequent courses has also been described for children with leukemia versus those with inherited diseases; 3.16 and 2.7h versus 1.93 and 1.71h, respectively.176 Although these changes in PK might be related to enzyme induction, others deny such alterations related to sequential administration.177 One of the most extensive studies in the very young age group has been reported by Nakamura et al. They examined 1028 samples from 103 children with a median age of 18months (range 2months to 11years).178 They reported the peak of highest clearance at 24months of age.
In a single study PK parameters were collected from 46 children (median age 3.0, range 0.25–16.2years). Mean volume of distribution at steady state was larger in children <4years of age than in older children. Total body clearance was not different for the various ages. However, compared with older children, mean weight-adjusted clearance was higher in children <4years of age (3.8±1.40 versus 3.0±0.76mL/minkg).80 Modeling studies suggested that oral clearance expressed per kilogram of body weight is low in early infancy. Clearance increases to a maximum at approximately 2years of age, but decreases later on.62 Despite differences in clearance Vassal et al. were able to achieve for all children acceptable AUC if dosing was performed according to weight strata: 1.0mg/kg for <9kg; 1.2mg/kg for 9 to <16kg; 1.1mg/kg for 16–23kg; 0.95mg/kg for >23–34kg; 0.80mg/kg for >34kg.179 This is in line with findings from Schechter et al. and was related higher GSTA1–1 expression in the intestinal wall in young children.[173], [180]
To limit at least the variability in absorption the intravenous formulation is currently often used. In a recent study investigating intravenous busulfan in 24 children (including three in the age range from 0.4 to 0.6years and five in the range from 1.1 to 1.9years) no significant differences in clearance were found in relation to age. However, this study supports the finding by Dale et al. to use lower dosages in infants <10kg.181 Dalle’s report gives data on 14 infants below the age of 1year. They advise a starting dosage of 0.8mg/kg followed by adjustments based on PK determinations.174
Melphalan
In children melphalan, an alkylating agent, is only used in conditioning prior to stem cell grafting. It is only administered intravenously. When given orally, melphalan absorption from gastrointestinal tract is highly variable.182 The drug is for 70–80% bound to plasma proteins and is metabolized in the liver into monohydroxy-melphalan and dihydroxy-melphalan. After the formation of carbonium metabolites the two bis-2-chloorethyl groups bind covalently to guanine and induce DNA cross-linking. Further metabolism results in mono- and bishydroxyethyl products with no cytostatic activity. Elimination half-life in adults is about 1h.[183], [184] Renal clearance is hardly important considering the limited excretion in the urine (about 10–15%).[185], [186]
Goyette et al. compared PK in adults and children and their findings showed similarity. Of the 20 children only one child was below the age of 2years (1year 10months). There was a difference for those children who were on furosemide treatment and those not on furosemide, indicating that those on furosemide had a lower plasma clearance.113 In case of the simultaneous use of carboplatin, lower doses of carboplatin are needed to achieve a similar AUC. These data on the combined use were derived from a modeling study incorporating 59 children with an age range of 0.3–18years. The number of patients below the age of 2years could not be recovered from the report. Covariates included in their models were weight, carboplatin use and glomerular filtration rate.187 Also total body irradiation was found to be a factor in melphalan clearance.188 No statements on dose recommendations can be made in infants based on these reports.
Antimetabolites
Cytosine arabinoside (Ara-C)
After oral administration only a small fraction of Ara-C is absorbed. As a consequence, this drug is given intravenously or subcutaneously. Protein binding is limited and as a result the distribution volume is 0.7l/kg; Ara-C doesn’t penetrate the blood–brain barrier. It must be converted through a cascade of phosphorylation reactions into Ara-C-triphosphate (ara-CTP), which blocks DNA-polymerase activity and ribonucleotide reductase, and most importantly it is incorporated into the DNA.189 For entry in the cell the nucleoside transporter 1 (hENT1) is needed. The rate limiting step in the activation pathway is the intracellular saturable enzyme cytidinedeoxy kinase (cDK). It has been found that Ara-CTP levels are higher in leukemia cells as compared to normal lymphocytes.190 PK and pharmacodynamics are influenced by the type of leukemia. Both cDK and hENT1 can be different for the specific leukemia cells and the stage of the disease. A metabolite of Ara-C is Ara-U; which is not further phosphorylated and not incorporated in DNA. Plasma Ara-U inhibits Ara-C deamination and by this enhances Ara-C activation.191 The half-life of Ara-C is 7–20min. The metabolites (mainly Ara-U) are renally excreted, and only 10% is excreted as Ara-C.
In leukemia cells in children the activity of cDK is the rate limiting step. Avramis et al. described in 8 children (age ranges 0.75–16years) that cDK activity is similar to the activity found in adults.[192], [193] The rate of conversion of Ara-C to Ara-U has however a linear relation with patient age. This results in an increased Ara-C clearance observed in older children as compared to infants.194 In infants with ALL a 2-fold lower level of cDK-mRNA, but a 2.5-fold higher mRNA of hENT1, responsible for Ara-C membrane transport has been described. The mRNA expression of hENT1 was found to correlate inversely with in vitro resistance to Ara-C. An oligonucleotide microarray screen comparing patients with mll- gene-rearranged ALL with those patients with non-mll-rearranged ALL also showed a 2.7-fold higher hENT1 mRNA expression in patients with mll- gene-rearranged ALL (p=.046). This probably explains the high sensitivity in infant ALL to Ara-C.195 Also other factors such as concomitant medication and characteristics of the malignant cells can result in changes both in extra- and intracellular pharmacokinetics. For example, administering Ara-C after fludarabine, augments in children the intracellular Ara-CTP levels.196 In a study on 3 infants (0.64–0.9years) median systemic clearance was not different from 64 children of older age (1–19years).197 The general advise to decrease dosages with 50% is therefore not supported by the available pharmacokinetic data.6 As can be concluded from data mentioned above, statements on PK in infants are hard to predict. Data on the age-related differences in activity are partly known and especially in the induction phase of remission differences related to the metabolism of the malignant cells probably play a major role.
Gemcitabine
Gemcitabin is given only intravenously. The drug is metabolized in the liver, kidney, blood and other tissues. Like Ara-C, gemcitabine has to undergo intracellular phosphorylation by DCK into active diphosphate- and triphosphate forms. The penetration into the cell is substantially higher than Ara-C and the same holds for intracellular retention. The anti-tumour activity differs from Ara-C and is broader.[198], [199], [200] The killing effects of gemcitabine are not confined to the S-phase of the cell cycle. The diphosphate substrate is an inhibitor for ribonucleotide reductase resulting in depletion of the nucleotide pool and it makes, after incorporation into the DNA, the cells resistant to DNA repair enzymes.[199], [201], [202] This effect has been shown to enhance the cytotoxic effect of concomitantly given other cytostatic drugs. Metabolites are excreted renally and represent over 90% of the administered drug. PK data in children were reported by several authors. However, the youngest child was already 2years at study entry.[203], [204], [205]
Methotrexate
Methotrexate is the most common used antifolate. Mode of action is inhibition of dihydrofolate reductase leading to depletion of reduced folates, which interferes with purine metabolism. This is not the single way methotrexate exerts its activity. Methotrexate is converted to polyglutamates in both the liver and intracellularly in various tissues/cells. Polyglutamated dihydrofolate and 10-formyldihydrofolate metabolites are potent inhibitors of thymidylate and purine biosynthesis.[206], [207]
Methotrexate is absorbed from the gastro-intestinal tract by means of a saturable active transport system, resulting in lower bioavailability at high dosages. After entry of the portal vein, the drug is polyglutamated and stored in the liver. Distribution approximates total body water. Penetration to the central nervous system is not sufficient to reach adequate levels for kill of malignant cells. Methotrexate (and Ara-C) are the standard drugs given intrathecally. Based on the distribution of volumes in the subarachnoidal space; which are highly age dependent, specific age related dosages are applied. Methotrexate is metabolized into 7-hydroxy-methotrexate by aldehyde oxidase in the liver. This product can be polyglutamized in the liver. However, only a small percentage of methotrexate is metabolized into 7-hydroxy-methotrexate. This enzymatic step is more active at younger ages as can be concluded from higher concentrations of the metabolite.208 This metabolite is excreted in the bile, but in high dose methotrexate treatment, it is found in the urine as well. Bile excretion is inhibited by simultaneous administration of dactinomycin, folic acid, 5-methyltetrahydrofolate, rose Bengal, sulfobromophthalein, deoxycholate and conjugated taurocholate salt, which is indicative for an active drug transport. There is enterohepatic reabsorption of methotrexate. Another metabolite is DAMPA, which is probably formed by bacterial carboxypeptidase in the gut.
As mentioned earlier two modes of action are assumed, i.e. anti-folate activity and polyglutamation. Which of both cytotoxic mechanisms are most relevant remains unresolved up to date. The suggestion that the favorable prognosis of leukemia’s harboring the TEL-AML1 translocations is correlated with the higher concentrations of polyglutamates is tempting.209 Whether the poor prognosis in infants with ALL is related to methotrexate insensitivity is still unsettled. Polyglutamates can reside in the cells and be active for a prolonged time. The time these compounds exert their action varies between various tissues and malignant cells. Concomitant administration of other cytostatic drugs can significantly change the PK of methotrexate. For instance simultaneous administration of Ara-C induced methotrexate levels in erythrocytes, that were only a fraction of the levels in concomitant use of Ara-C.210 Simultaneous administration of etoposide increases methotrexate levels in the blood significantly.211 The drug is excreted in the urine; the amount of excretion is dependent on the dosage. With the use of lower dosages excretion percentages as low as 44% are found, whereas with high dose therapy, nearly 100% of the drug is renally excreted. Renal excretion occurs both through glomerular filtration as well as tubular excretion of unaltered methotrexate. Part of the methotrexate is re-entered due to tubular absorption. Alkalinization of the urine inhibits tubular reabsorption. Elimination half-life depends on the doses given. For adults treated with low dose methotrexate 3–10h and for high dose 8–15h has been reported. Decrease in renal function results in lower clearance rates and increased toxicity.
PK in ALL revealed increments in methotrexate clearance from the first 3months after birth (84±30ml/min/m2) onwards to even 160±71ml/min/m2 in adulthood.[197], [212], [213], [214] High clearance rates were already reported in the age range 1–3years.214 Comparing children of less than 10years of age versus older children a decreased clearance in the older age cohort has been reported.214 A study specially focusing on infants (n=103) reported that clearance tended to increase with age in these infants, and that boys had higher clearance rates than girls, 6.77 and 5.28L/h/m2 (P=0.030).215 As a consequence, it can be concluded that clearance increases during the first year of life, but declines thereafter. The decrease in hydroxylation at an older age, as described by Borsi et al. may be an explanation for this decrease later on.208 In a study of 16 infants (2months to 1year) dosage dependent clearance was suggested with significantly lower clearances at higher dosages. The authors propose allometric dosing schemes using body surface adjustments.197 Data on the levels of methotrexate-polyglutamates in infants are rare. In the study of Ramakers-van Woerden et al. levels are lower in the 8 children below the age of 1year, but findings did not reach significance. The authors do not link methotrexate resistance with alterations in metabolism.216 Similar to the situation in Ara-C efficacy this finding is probably related to the type of leukemia.
Pemetrexed
Pemetrexed is a novel antifolate inhibiting the biosynthesis of thymidine and purine nucleotides, targeting at thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.[217], [218] Following intravenous infusion, it is also polyglutamized. After cell entry a prolonged retention and enhanced target interaction is claimed. As such a greater efficacy as compared to methotrexate is assumed.[219], [220] The drug is excreted renally. The role of this antifolate in pediatric oncology is still under discussion. The drug was well tolerated in a study of 31 children (age range 1–21years; median age of 12years with refractory solid tumors.221
6-Mercaptopurine
6-Mercaptopurin is the most often orally prescribed drug. Other forms of administration are rectal and intravenous; and for both the first pass effect is absent and systemic exposure is substantially higher.222 6-Mercaptopurin (6-MP) is a structural analog of hypoxanthine. Bioavailability of 6-mercatopurin is highly variable. Following oral dosing dosing bioavailability is only 5–37%.223 This is, however, not related to absorption, but is a consequence of very early decay of the drug, due to high activity of xanthine oxidase in the intestinal wall. The distribution exceeds total body water (i.e. 0.9l/kg). Concomitant use of allopurinol gives a steep increase in bioavailability.224 Increasing the oral dosage results in a disproportional increase in bioavailability indicating a saturable first pass effect.225 Several metabolic routes occur. One of the most important ones is intracellular activation into 6-MP ribose phosphate, which inhibits de novo purine synthesis. 6-MP also converts to 6-MP ribose triphosphate, which is incorporated in DNA and RNA. It was shown that cytotoxicity is best correlated with the quantity of 6-MP metabolites incorporated in the DNA.226 6-MP is cleared from the body by oxidation into inactive 6-thiouric acid by xanthine oxidase and methylation by thiopurine methyltransferase (TPMT) into 6-methylMP. Since there is no negative correlation between levels of methylated forms and 6-thiouric acid, there are probably more modes of decay of the drug. The decay of 6-MP by TPMT activity is subject to genetic polymorphism.227 Several variants have been described; TPMT∗3A, TPMT∗3B and TPMT∗3C being the most important ones to consider. TPMT∗3A is the most common variant allele in Caucasian subjects (frequency approximately 5%), TPMT∗3C is the most common variant in East Asian subjects (frequency approximately 2%). Single-nucleotide polymorphisms (SNPs) have been sorted out for these variants. In both TPMT∗3A and ∗B there is an Ala254Thr alteration. In TPMT∗3A and TPMT∗3C Tyr240Cys is the (for TPMT∗3A additional) alteration found. Both TPMT∗3A an TPMT∗3B result in virtual lack of enzyme activity. The decrease in activity in case of a TMPT∗3C variant is less pronounced.[228], [229] In homozygous TPMT∗3A patients very substantial dose reductions are needed. In heterozygous patients reductions are often intermediate.230 ALL patients with high TPMT activity and/ or a wild type TPMT gene are prone to a higher risk of relapse.231 There is renal elimination of the metabolite thiouric acid, whereas less than 10% of the drug is excreted unaltered in the urine. Excretion is different for intravenous versus oral administered 6-MP. In children 21% of unaltered 6-MP is found in the urine after intravenous administration versus only 7% after oral ingestion. In case of concomitant use of allopurinol 42% urine excretion has been documented.232 Due to the high inter-patient variability of metabolism (especially in relation to TPMT activity) in clinical practice white blood cell counts are used as surrogate marker for adequate dosing. Kinetic studies are sparse. In a study of 3 infants (0.58–1year) the variability in metabolites was substantial and comparison with 103 older children did not reveal statistical significant differences.197 Balis et al. included patients with ALL in the age range from 1.1 to 17years of age and observed no age related changes in blood levels.233 Since 6-MP is mainly used in maintenance treatment of malignancies; dosing is performed according to white blood cells values. As a result the alterations in dosing according to age (and in according to TPMT activity) are in fact covered by these dosing adjustments.
6-Thioguanine
6-Thioguanin (6-TG) is closely related to 6-MP. Both drugs are mainly used in the treatment of leukemia. 6-TG has quite similar mode of action and metabolism as 6-MP. It is however more directly converted into thioguanine nucleotides. Bioavailability of 6-TG is variable; variations between 14% and 46% are reported. CNS penetration is similar to 6-MP and using continuous infusions intrathecal cytotoxic drug levels can be achieved.234 6-TG gives lower peak plasma concentrations in comparison with 6-MP. Some studies report a higher susceptibility of in vitro leukemic cells for 6-TG.[235], [236] Metabolism differs from 6-MP, since 6-TG is not a substrate for xanthine oxidase, but it is converted into the active metabolite 6-thio-inosine by guanase. As a result allopurinol doesn’t block degradation as is the case with 6-MP. TPMT induced methylation is more extensive than 6-MP, but that product is less active then 6-TG itself. Since no thiouric acid is formed due to absence of the xanthine oxidase mediated step, there is mainly hepatic clearance of the drug. Less than 10% of the drug is excreted unaltered in the urine.
Studies comparing 6-MP and 6-TG in children with ALL, showed that the main metabolites of 6-TG were thioguanine nucleotides, whereas during 6-MP treatment methylated thioinosine nucleotides predominated. Levels of methylated thioguanines were even 26-fold higher. The median thioguanine nucleotides concentration was about 7-fold higher in the thioguanine branch. In contrast to 6-TG, the pattern of metabolites administering 6-MP shifted toward the methylated ones with increasing dose.237 In a randomized study there was no difference in outcome in children on 6-MP versus 6-TG.237 In another study comparing 6-TG and 6-MP, 2027 patients with acute lymphoblastic leukemia were randomized.238 A significantly higher EFS (84%; versus 79% for 6-MP) was found; however, overall survival was similar 91.9% and 91.2% respectively. In the 6-TG group 25% of patients developed a sinusoidal obstruction syndrome and these patients were switched to 6-MP treatment. Similar to 6-MP drug dosage is based on white blood cell count during therapy. In a comparison of Down-syndrome children (median age 1.8year; range 1.1–3.3years) versus non-Down syndrome children with acute myeloid leukaemia (median age 11.0years; range 0.5–17.7years) the administered dosage of 6-TG was substantially higher in the latter group. The same authors also compared the amount of drugs given to non-Down children <2years of age (n=5) versus the 35 children above that age. The total dosage needed to achieve comparable blood levels was about 75% of the dosage given to older children.239 However, the relevance of determining blood concentrations can be questioned since 6-TG concentration was in both univariate and multivariate analysis not an independent factor for CR.239 Similar to 6-MP, dosages are titrated on basis of leukocyte counts. There are no data specific for infants.
5-Fluorouracil
After intravenous administration 5-fluorouracil rapidly penetrates the extracellular space and the cerebrospinal fluid. The volume of distribution exceeds slightly extracellular fluid space. Fluorouracil is in the cell activated through formation of 5-fluorodeoxy-uridine-5-monophosphate and 5-fluorouridine-5-phosphate. It exerts its action at the moment it is incorporated into RNA. The drug further inhibits thymidylate synthetase. To a lesser extent it is incorporated into DNA. Decay of the drug takes mainly place in the liver. Fluorouracil is often used in adults in combination with leucovorin in order to enhance activity.240 Excretion is almost completely via the hepatic route.
Currently instead of fluorouracil its prodrug, cepacitabine, is often used. Both fluorouracil and cepacitabine are seldomly used in pediatrics. A phase 1 trial, including 35 evaluable patients (median age 9years; range 1–21years) with refractory malignancies, confirmed applicability of similar dosage of fluorouracil in children as in adults. In respect to the concomitant used leucovorin, the total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid were approximately the same as in adults, even though the Cmax of each compound was lower.241
CYP2A6 is a major enzyme in 5-fluorouracil metabolism and enhances the activation of the prodrug tegafur.49 As a result if ever 5-fluorouracil treatment in infants is indicated, this orally taken prodrug is not a good choice.
Fludarabine
Fludarabine is only given by the intravenous route and is quickly metabolized. Peak values of the dephosphorylated metabolite are reached within 30min. Elimination is for 40–60% via the renal route. In animals radioactivity after labeling of the drug was fully recovered from the urine. Fludarabine is the monophosphate analog of adenosine-arabinoside. After infusion it is fully dephosphorylated. In this form it enters the cell and it is phosphorylated into fludarabine triphosphate. There are indications that fludarabine is also able to inhibit RNA polymerases and depletion of nicotinamide–adenine-dinucleotide, which results in decrease in cellular energy stores and interferes with the DNA repair process.[242], [243], [244] As a result the activity of fludarabine is not limited to the S-phase. Due to the depletion of deoxynucleosides due to inhibition of ribonucleotide reductase there is a decreased inhibition of cDK, which results in case of co-administration of Ara-C in augmented Ara-CTP levels. There is linear renal clearance and 50–60% is recovered in the urine, whereas no metabolites are detected.245 In children the terminal half-life was similar to adults, while the total body clearance was shorter than reported for adults receiving bolus or continuous doses.246 In 31 patients (median age 8years; range 1–19years) cellular Ara-CTP levels augmented 5–8-fold in leukemia cells from patients receiving fludarabine phosphate treatment followed by Ara-C.246 No specific infant data are available.
Cladribine
Cladribine is usually administered intravenously. After subcutaneous administration there is 100% bioavailability. Intracellular concentrations were found to be several hundred-fold higher than plasma concentrations.
Cladribine is a chlorinated adenine analog. After cell entry it is phosphorylated by deoxycytidine kinase. In cells with a high content of deoxycytidine kinase the metabolites are incorporated in DNA inducing strand breaks. There is further inhibition of ribonucleotide reductase, which is an additional negative factor for DNA synthesis and repair.[247], [248] Fifty percent of the drug is eliminated by renal excretion.249 In a pharmacokinetic study of 25 (mostly pediatric) patients (median age 9.6; range 0.7–23.3years) it was shown that clearance per body weight was lower in older children, but after correction according to body surface the differences disappeared.250 A study in 49 children (median age 9.8years; range 0.4–20.2years) on the simultaneous administration of Ara-C and cladribine showed an increase in intracellular Ara-C metabolite concentration. The clinical relevance of this finding is, however, debated.251 As with other cytostatic drugs, who are actively transported the (malignant) cells, pharmacokinetics, but especially pharmacodynamics are hard to generalize for infant malignancies. Dosage adjustments should e related to renal function because of the important role of renal function in clearance of the drug.
Antimitotic drugs
Vinca alkaloids
The primary mode of action of vinca alkaloids is the interaction with tubulin, but other effects are noted as well; such a competition for amino acid transport into the cell, inhibition of RNA, DNA and protein synthesis, disruption of lipid metabolism, increase of oxidized glutathione, inhibition of glycolysis, altered release of antidiuretic hormone, inhibition of histamine release, augmented adrenaline release, inhibition of calcium–calmodulin-regulated cAMP-phosphodiesterase and disruption in the integrity of the cell membrane and its function.[252], [253], [254] The effects on tubulin interruption vary with age.255 Dosages of the various alkaloids are different. Vinca alkaloids have to be administered by the intravenous route in infusions, only vinorelbine can in children be given in an oral formulation.[256], [257], [258] Bioavailability of the oral formulation is however only 25–40%.[259], [260] Vinca-alkaloids have quite similar PK characteristics, with a tri-exponential profile of clearance. Volumes of distribution are large and there is high tissue binding. Intracellular concentrations are substantially higher than plasma levels. CYP 3A4 is one of the enzymes involved in the metabolism of vinca alkaloids.[261], [262] A terminal t½ up to 84h reported for vincristine. Clearance for all products is hepatic, resulting in biliary/fecal excretion. Side effects differ among the various alkaloids.
Studies in children revealed high inter-patient variability in PK. In a study on vincristine monotherapy, the clearance was substantially lower as compared to children who were on steroids. This observation is very important for children because corticosteroids and vincristine are the main component of anti-leukemia therapy The inter-patient variability is not fully explained, but for the differences in children receiving steroids versus those not on steroids the induction of CYP3A4 by steroids may be explanatory.[112], [263], [264], [265], [266] Whether this induction is seen in infants is unknown. There is a difference in metabolism of vincristine with respect to characteristics of the malignancy. Hyperdiploid (with >50 chromosomes) leukemia patients showed a faster clearance of vincristine as compared to diploid or hyperdiploid (46–50 chromosome) cases.263 In infancy leukemia with hyperdiploidy >50 chromosomes is not a prominent subtype. Since, hyperdiploidy >50 chromosomes is a factor correlated with better outcome, the relation of PK of vincristine versus outcome remains to be clarified.[267], [268] Neuropathy could not be related to PK parameters.264 In children above the age of 1year some relation of younger age and lower clearance is suspected, but in multivariate analysis this seemed not to be significant.265 Similar observations were done by others.269 In infants <1year only limited data are available. Crom et al. reported on vincristine use in two 2months old infants, and they found that when clearance was normalized to body surface area, the clearance in these infants was much slower than in older children. If normalized for body weight the clearance approached the findings of older children 16.7 versus 20.6ml/min for children 2–10years of age.264 Based on these findings posology should be based on weight, rather than a simple decrease by 50% on top of dosing according to body surface area as used in literature.6
Taxanes
Taxanes are given by intravenous infusions. Oral administration is possible, but only in conjunction with oral modulators of ABC transporters (e.g. cyclosporine) and/or cytochrome P-450 mixed – function oxidases to decrease the effects of first pass absorption and metabolism in the intestine and liver. Taxanes bind to all tissues, except for the central nervous system tissues. This results in large distribution volumes and a short distribution t½ and protracted terminal t½ values. Elimination is though the hepatobiliary system.
Paclitaxel: Primary mode of action is binding to the microtubules. As a result there is bundling of microtubules within the cells, resulting in a mitotic block at the metaphase-anaphase of the cell. Paclitaxel is less potent than the related docetaxel.255 Paclitaxel is metabolized by CYP450 (mainly 2C8 and 3A4) and excreted in bile.41 One of these products is 6-alpha-HO-paclitaxel; a metabolite with only very limited cytostatic potential.[270], [271] The parent compound is a minor part of the drug excreted. There is a negligible penetration in the central nervous system.[270], [272] Data in children are scarce; and for infants hardly any data are available.[271], [273], [274] In the phase I study of Doz et al. 17 patients were included with an age range of 1.6–19years (mean 9years).275 The phase I study of Horton et al. was done in 63 patients with an age range of 0.8–23years.276 Major side effects are hematological toxicity and hypersensitivity. Peripheral neuropathy is the most limiting factor for use in children.275
Data on docetaxel are even scarcer. Docetaxel is metabolized to inactive oxidation products, mainly by the CYP3A4/5.41 The metabolic activity is influenced by polymorphism of these genes.277 In the report of Franklin et al. from the Children’s Oncology Group (COG) 12 children with leukemia were included (mean age 6years, range 1–21years).278 A study on solid tumor pediatric patients included only patients from the age of 2years onwards.279
For infants dose recommendations on the use of taxanes cannot be made.
Topoisomerase inhibitors
In humans 3 topoisomerase families are known.280 Topoisomerase inhibitors exert their action through transesterification, in which a phosphoester-bond is transferred to a specific enzyme generating breaks in the DNA backbone. Type 1 enzymes make breaks in single stranded DNA, type 2 enzymes make breaks in double-stranded DNA. As a result of both the replication of DNA is interrupted. The currently used inhibitors, etoposide and teniposide, belong to the type 2 family. The camptothecans (topotecan, irinotecan e.g.) belong to the type1 family. Although many cytostatic drugs have topo-isomerase activity, e.g. anthracyclines and actinomycin, their activity is not specific enough to be categorized among topoisomerase inhibitors.281
Etoposide
In children etoposide is given by intravenous infusion. Oral administered etoposide has a highly variable bioavailability, and in pediatrics it is only used in palliative settings. After infusion etoposide is for >90% bound to plasma proteins. There is hardly any penetration in the central nervous system. Etoposide is metabolized into several products, with the major product being etoposide–glucuronide. A metabolite with cytotoxic activity is the O-demethylated one, which is formed in the liver. CYP3A4 is an important enzyme for the conversion into this product.282 Most metabolites are broken down into quinones. This is probably under the influence of CYP3A5 activity. Other enzymes involved in the metabolic process are CYP1A2 and 2E1.[41], [277] Concomitant medications such as steroids and anti-epileptic drugs, do influence PK due to induction of CYPs.112 Elimination is by hepatic clearance, about one third of the drug/metabolites is cleared by the kidney.
Despite the fact that the PK in children of various ages is quite similar, dosing according to the body surface area has been shown to result in 8 out of 33 cases to either under- or overdosing of the drug.[283], [284], [285], [286], [287] The authors showed that only an equitation introducing peak level, duration of infusion time and a Cr-elimination rate constant predicted the AUC appropriately.288 In a study including 4 children ranging in age from 0.5 to 1.8years the clearance rate was not substantially lower than in older individuals.283 Observations in 2 infants (0.5years and 1year of age) suggested that systemic clearance increases with age. In the same report children >1year were also assessed. In these older children no relation of age and clearance was found.197 In a recent report on the combined use of carboplatin and etopside in 19 children with 4 below the age of 6months and 13 below the age of 13months, an equation relating clearance to body weight was formulated.287 These data appear sound for children above the age of 6months; however, in the very young infants the limited glomerular filtration rate may require further prudence.
Teniposide
Similar to etoposide there is a variable bioavailability after oral administration, i.e. smaller dosages have higher bioavailability. After infusion teniposide is highly bound to plasma proteins (>99%) resulting in a high volume of distribution. There is hardly any penetration in the central nervous system. A limited amount of the parent compound is excreted in the urine.289 Enzymes involved in the metabolic process are CYP3A4 and 3A5.41 Major metabolites in children are hydroxic acids.290 Elimination is by hepatic excretion, but after 140h about 45% of radioactivity of radio-labeled teniposide was recovered in the urine. There is an inverse correlation between ALAT levels and clearance of the drug, indicative of metabolism in the liver. Excretion in the faces is limited (about 10%).
In a pediatric study of children ranging from 4.86 age onwards, t½ was 8.95±3.73h, which is a bit shorter then reported in adults. However, t½ was dose independent.[281], [291] In a study including 6 pediatric patients, no age specific PK differences were mentioned (the youngest being 3.7years).292 In a study on 3 infants (ages 0.64–0.87years) normal clearance rates were found. As a result normal dosing based on body surface was advised.197 In young infants below 6months dose reductions seem sensible, however no specific guidance can be given on basis of limited data.
Topotecan
Topotecan can be administered both orally and intravenously. Oral administration is highly variable due to the effect of drug transporters, food and high pH in the bowel, leading to conversion to the carboxylate form. Bioavailability after oral administration is only 35–50%.293 Addition of inhibitors of drug transporters results in an increased bioavailability. Adding drug transporters inhibitors results in increased bioavailability. Penetration of the central nervous system gives levels of about one third of the systemic levels. After absorption the lactone ring of topotecan undergoes rapid hydrolysis and carboxylate derivatives are formed.294 Involved in this process is probably CYP3A4.41 These carboxylate derivatives have no cytostatic activity; since an intact lactone ring is essential for the interaction with topoisomerase1.293 Eighteen percent of intravenously administered topotecan is found in the feces. In pediatric studies 90% of the product and carboxylate derivates could be recovered from the urine (25–50% within 24h).[295], [296] In the urine also a O-glucuronidation metabolite and a N-desmethyl metabolite were recovered.[297], [298]
Biliary excretion is limited and is not very effective for ultimate excretion from the body due to enterohepatic recycling.[293], [299], [300] Elimination half-life t½ of the parent drug ranges from 1.6 to 5.5h. Median t½ after oral administration was 4.1h.301
Studies in children have not indicated any differences in pharmacokinetics as compared to adults.[295], [302], [303], [304], [305], [306], [307], [308], [309], [310] In the studies of Athale et al., Blaney et al., Frangoul et al., and Santana et al. a number of children of 1year of age were studied. However, the exact number of these infants remains uncertain.[302], [303], [305], [307] Panetta et al. developed a PK model in neuroblastoma patients as young as <1month. Median age of the group assessed for modeling was 3.1year. They felt no need for inclusion of age as factor.311 However, in the description of another modeling experiment by the same group of researchers an age <0.5years was a covariate in case age was used as a categorical factor.312 Based on these findings and based on data on ontogeny additional dose reduction in infants are advised.
Irinotecan
Irinotecan is usually administered intravenously. Despite the large distribution volume, the penetration in the central nervous system is nearly absent, but its metabolite idarubicinol penetrates the blood–brain barrier, and CSF levels approach those reported as being cytotoxic to human tumor cell lines.313 Irinotecan is a prodrug requiring enzymatic cleavage by carboxylesterase converting enzyme to form the active metabolite SN-38. Both the parent drug and SN-38 undergo reversible hydrolysis of the lactone ring.314 Other enzymes influencing metabolism are 1A3, 1A7, UGT1A9, 1A10 and ABCC2.[41], [315] Elimination half-life of SN-38 (8.7h for SN-38) is substantially longer then for irinotecan.[316], [317] Additionally irinotecan undergoes oxidation via CYP3A4 and 3A5 to relatively inactive, but toxic metabolites. One of these metabolites can be converted to SN-38 by carboxylpeptidase.[41], [318], [319] SN-38 is primarily glucuronidated and inactivated by UGT1A1 and excreted in the bile. In addition there is enterohepatic circulation.320 About a quarter of the parent drug is excreted in the urine.
A few reports on PK provide data in children. From 3 studies done by the COG it becomes apparent that children below the age of 10years have an increased clearance of SN-38. Although not a linear correlation was described, the graphs show a clear increment at the younger ages. The authors sought an explanation in the higher ratio liver versus body weight. Other factors, however, may be important as well; such as an altered enterohepatic circulation and age related alteration of the activity of metabolic enzymes. As such the decreased activity of CYP3A4 and UGT1A are good candidates for such an explanation. Increased bilirubin levels were found to be related with a decreased clearance. Unfortunately no data on children below the age of 1year were included.321 Bomgaars et al. studied PK in 79 pediatric patients (median age 9years, range 1–23years). Although reported in adults they did not find a relation of UGT1A1 genotype versus neutropenia and gastro-intestinal toxicity. However in children a high inter-patient variability in clearance, conversion and glucuronidation was reported.322 Vassal et al. studied 81children ranging from 0.9 to 18.5years (median 8years). They found no differences in relation to PK in relation to age.323 Based on these reports no clear statements can be made on very young infants. Based on the decreased activity of UGT1A1 in the very young children allometric dosing might result in increased toxicity. From the age of 0.9years allometric dosing might result in lower levels of activity.
Anti-tumor antibiotics
Doxorubicin and daunorubin
The mode of action of all anthracyclines is in principle 4-fold: activation of protein C-kinase-mediated signal transduction pathways, generation of oxygen intermediates, stimulation of apoptosis, and inhibition of DNA topoisomerase II catalytic activity. All anthracyclines, as well as mitoxantrone, show prolonged tissue binding.
After intravenous administration daunorubicin is bound for about 60% to plasma proteins. Rapid distribution to the tissues, especially liver, lungs, kidneys and heart occurs. There is no penetration in the central nervous system. The concentration in leukemia cells can be substantially higher. Up to 700 times higher intracellular levels as compared to plasma levels were reported. The drug is eliminated for 25% as active drug in a period of 5days. Excretion in the bile is more important than excretion in the urine (only 25%). Distribution of doxorubicin is similar to daunorubicin, except that the renal excretion is lower; i.e. 10%.
Doxorubicin: In plasma the parent drug predominates. The drug is a substrate for CYP2D6 and CYP3A4.41 The most important metabolite is doxorubicinol, which is only present in limited amounts. About 50% of the drug, its metabolites, including aglycones, and the glucuronidated and sulphated forms are excreted in the bile. There is extensive binding to DNA and proteins, leading to a terminal t½ of 30–50h. Modeling experiments indicate that there is an increased clearance at younger ages. Since the youngest person was only 17, the applicability for the pediatric age range can only be extrapolated.324 Others did not reveal shifts in Cmax in relation with age.[325], [326]
In children PK is highly variable. In the report of Frost et al. in 107 children from 1.3 to 17.3years of age (median 4.7years) highest median peak plasma concentrations were found in 4–6year old children (77ng/ml). Children below the age of 2years (n=10) and those >6years had values below 50ng/ml. Doxorubicinol/doxorubicin ratios varied from 0 to 0.81 (median 0.13).327 Another study by a Swedish group was done in children with AML. Four children below the age of 2years had similar blood levels on lower dosages as compared with the 33 children above that age, they needed higher dosages to reach similar blood levels. No differences in doxorubicinol/doxorubicin ratios were found. A separate group of four Down syndrome patients showed 65% lower doxorubicin levels as compared with non-Down patients. However, this was due to dose reductions. In these four children clearances were similar to non-Down patients. Therefore they did not recommend dose reductions for patients with Down syndrome. The authors further demonstrated a clear correlation of plasma clearance and efficacy of induction treatment for the whole group of patients in their study.328 A decreased clearance of doxorubicinol has been demonstrated in children with a body fat percentage over 30%. The clearance of the parent drug was not influenced by the composition of the body. Infants experience cardiotoxicity after lower dosages. Doxorubicinol might contribute to cardiotoxicity. Whether cardiotoxicity is related to fat percentage related volume of distribution of doxorubicinol is hard to conclude since the authors only included children from 5.7years onwards.329 In a study including 8 children below the age of 2years significantly lower clearances were found as compared to 52 older children. Sorting out the 4 children below the age of 1year (0.17–0.83years) significance was lost, which was probably due to the small numbers.197
Daunorubicin: In contrast to doxorubicin, the parent compound is rapidly cleared and daunorubicinol is the predominant active compound in the plasma. Similar to doxorubicin there is extensive binding to DNA and proteins. Metabolic pathways are similar to doxorubicin. Clearance has been shown to be delayed in children <10years. In 8 children <2years of age clearance was even slower. However, statistical analysis did not reveal significance for these very young patients.197 Data on PK of daunorubicin in infants are very scarce. The advise to consider full dosing from 3 to 6months should be taken with some caution considering the lower clearance below the age of 2years.6 This is supported by the recent publication of Hempel et al. they investigated 21 patients with ALL (age range 0.05–1.88years; among them 5 infants <0.5years and 15 ranging in age from 6 to 12months) and the authors compared the data with findings in older children (age range 1.6–18.8years). Body surface area corrected pharmacokinetic data were not different between both groups. In the young children the daunorubicinol levels were substantial lower due to the dose reductions that had been applied in this age group. As a result age related dose reductions were not advised. What the effect of abstaining from dose reductions will mean for side effects, such as cardiotoxicity, is unclear.10
Liposomal constructs claim to be less cardiotoxic, but there are no data in infants to confirm.
Epirubicin
Distribution of epirubicin is similar to doxorubicin. Elimination is mainly in the bile; only a few percent of the drug is excreted in urine. The mode of cytostatic activity is similar to doxorubicin and daunorubicin. Metabolites formed in the liver are epirubicinol and glucuronides of epirubicine and epirubicinol. Eksborg studied PK in 31 children including children <2year. They found no correlation of PK data with age.326
Idarubicin
After intravenous administration, there is, similar to other anthracyclines, substantial tissue penetration. As a result there is a high volume of distribution and long terminal t½. In leukemia patients higher concentrations were found in the blood cells. Metabolic enzymes involved in the metabolic process are CYP2D6 and CYP2C9.41 The primary metabolite, idarubicinol, is cytotoxic and levels in the plasma are higher than the levels of the parent compound.330 Excretion is for 80% as 15-idarubicinol, and, the major way of secretion is via the bile. The mode of cytostatic activity is similar to other anthracyclines.
PK in a cohort with children ⩾1year of age were not influenced by the age as such.313 Another study providing details on PK measurements in patients >2years did not reveal any age-related changes in PK.331
Mitoxantrone
Mitoxantrone is an anthracenedione which is closely related to commonly used anthracyclines. It binds to nucleic acids and inhibits DNA and RNA synthesis. Mitoxantrone intercalation of DNA has a preference for GC base pairs,332 but also stochastic hindrance resulting in compaction of chromatin results in anti-tumor activity.333 The free-radical mechanism is less than in anthracyclines, which results in substantially less cardiotoxicity.334 Characteristics of mitoxantrone have high similarity as compared to anthracyclines. Similar to the doxorubicin and daunorubicin there is a high tissue binding, resulting in terminal t½ of over 60h. The known metabolites have no anti-tumor activity. Oxidation by CYP-450 enzymes has been claimed.335 Breakdown of the product is by oxidation to mono-and dicarboxyl acids.336 Within 5days 10% of the drug and metabolites are excreted in the urine, 65% as parent drug and the remaining 35% as metabolites. In the same 5days about 20% can be recovered from the feces.337 No pharmacokinetic data for infants are known.
Dactinomycin
Dactinomycin exerts it cytostatic activity by binding to DNA and inhibition of RNA and protein synthesis. After intravenous administration the drug accumulates in nucleated cells. Dactinomycin levels in the serum quickly decline as the drug binds to cells and tissues, leading to a prolonged half-life >40h in adults. No active metabolites were described. The drug is excreted through the urine and in the bile. Within 1week one third of the administered drug is found unaltered in the urine and feces, i.e. 20% and 14% respectively.
In a study on 33 patients (aged 1.6–20.3years; mean 9.9) age was analyzed as one of the covariates, but age was not found to influence PK.338 In a study in the United Kingdom 31 patients from the age of 1year onwards (median 7years) children showed that children below the age of 36months suffered more often from hepatotoxicity. There is an advice to decrease the dosage by in infants 50%.6 From the cited UK study, however, the number of PK samples from patients under the age of 3years was too low to make adequate PK assessments.339 Based on the high tissue binding it is even doubtful whether PK data will be very informative in relation to pharmacodynamic and toxicity data in infants. As a result a careful reporting of efficacy and side effects seem to be the most relevant points to assess dosing.
Bleomycin
Marketed bleomycin is a composite of multiple glycopeptides. Bleomycin complexes with several endogenous and exogenous metals and is activated after microsomal reduction. The drug exerts its action through cleavage of the DNA.340 The drug is metabolized by hydrolysis, taking place in several tissues. Lung toxicity is related with local hydrolysis of the drug in the lung. Bleomycin is only given in a few types of malignancies. After parenteral administration distribution of bleomycin to lungs, liver, kidney is very rapid. Forty to 70% is excreted in the urine 24h.[341], [342] Excretion is strongly linked to creatinin clearance.
PK data are scarce. In a study on 14 children PK were found to be similar to adults. Children with an impaired renal function had a more prolonged exposure to the drug. In the 3 children below the age of 3years elimination half-lives were a bit shorter then in older children, whereas total plasma clearances were significantly higher (70 versus 45m/min/m2) in older children.343 For infants no recommendations can be made.
Miscellaneous drugs
Cisplatin
Cisplatin and its analogs exert their action by covalent binding to purine-DNA bases, resulting in interference with normal function of DNA. After administration in 2h infusions 90% of the drug is protein bound. There is high penetration to tissues such as liver, kidneys, testicles, colon and small bowel. There is no penetration in the central nervous system. There is prolonged binding of cisplatin in the body. Even after decades platinum can be detected in treated individuals.344 Enzymes involved in the metabolic process are CYP2E1 and 3A4.41 An important route of renal elimination of cisplatin is conjugation with glutathion adducts.345 Elimination is for 90% renally in a combination of glomerular filtration and tubular secretion. Ten percent is eliminated by biliary excretion. Terminal t½ is several days (up to 240h are reported). The high variability in PK has been related to this binding.[346], [347] The variability has resulted in a recommendation in adults not to dose on basis of BSA, but instead to use fixed dosages.348 The amount of adducts of cisplatin with DNA are related with efficacy and toxicity.
However, in children no relation of adducts versus PK parameters of unbound or total cisplatin levels was found.349 Bues-Charbit et al. studied 4 children (16months, 18months, 6years and 12years). Median t½ was 81h, 35% of the ultrafilterable platinum was recovered from the urine within 48h, although after 10days the drug was still detectable.350 In a study on 21 children, including two children below the age of 2years quite different parameter came up with for instance a t½ of 40min. This might indicate that in older children the clearance is substantially higher as compared to infants. As a result the body surface area based dosing was severely questioned. Later an advice was formulated to categorize patient according to body surface area in one of the three groups (⩽1.65m2; 1.66–2.04m2; ⩾2.05m2).[351], [352] A weight, t½ and Cmax based equitation has been constructed covering the PK profile in a better way.353 Unfortunately no data on infants were obtained and dose recommendations are hard to give due to above mentioned factors.
Carboplatin
Mode of action is comparable to cisplatin. Major advantage is the reduced non-hematologic toxicity as compared to cisplatin. The formation of DNA adducts is lower. There is a linear relation between dosage and total amount of platinum in the plasma. It takes more than 24h to reach half of the peak level. Over 65% of carboplatin is excreted in the urine. Total body clearance correlates with glomerular filtration, but not with tubular excretion.
In 28 children (including 4 children <5years) the quantity of adducts could be correlated with AUC data. As a result PK data are more informative than in cisplatin. In 19 patients below the age or 15months with body weights below 12kg with neuroblastoma treated with carboplatin in combination with etoposide; carboplatin clearance values ranged from 12.8 to 33.6ml/min, with total AUC values of 4.2–9.3mg/ml.min achieved over the 3days of treatment. Comparison with historical data from children with a body weight above 12kg clearances were significantly higher in the smaller children.287 In a study starting with administration of standard dosages, dose adjustments had to be made in 75% of the children on basis of the observed AUC. The measured AUC’s were correlated with glomerular filtration rates.[349], [354] In a study in 57 children (median age 5years; range 2months to 18years) a complex equation was computed including weight and serum creatinin in order to predict the clearance rate of carboplatin. Applying this equation resulted in a significantly decreased alteration of dosing decreased from 74% to 29%.355 Also a simpler equation was constructed from data of 22 patients (including 4 infants <1year and 3 below the age of 2years) based on GFR and to a lesser extent on body weight.356 In the report of Picton et al. a preterm neonate with bilateral retinoblastoma was treated under drug monitoring. After increasing the dosages they observed that the AUC was not correlated with the dosage given. Doubling the dosage resulted in more than twice an increment of the AUC.357 Tonda et al. described in less than 1years of age, that carboplatin clearance per square meter is approximately 40% lower than seen in patients 1–4years of age.358
Oxaliplatin
Also oxaliplatin has many similarities with the other platin compounds (e.g. mode of action and renal excretion).359 After administration the drug accumulates in red blood cells and in plasma. The metabolism is not fully characterized, but the excretion is expected to be mainly renal. Oxaliplatin administration gives less formation of DNA-adducts. Further differences are presumed to be related to the different effect on DNA polymerase(s), mismatched repair activity, and Pt-DNA damage recognition proteins.360 In a pediatric study in 43 children (median age 8.5years; range, 0.6–18.9years) similar PK data were found as in adults.361
Formulation
It is generally assumed that children below the age of 6years experience problems with the swallowing of tablets and capsules. Due to local mucosal toxicity or due to the absence of gastro-intestinal uptake or limited or erratic gastro-intestinal absorption only a limited number of cytostatic drugs can be administered orally (often on maintenance basis). The formulation issue can form a tremendous hurdle and use of extemporaneous formulations are common practice. Data on bioavailability using these formulations are lacking and adequate dosing is merely based on assumptions. There are only tablets or capsules but no approved liquid formulations available for those drugs that can in principle be administered orally; i.e. cyclophosphamide, procarbazine, temozolamide, lomustine, chlorambucil, busulfan, melphalan, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine, vinorelbine, etoposide, topotecan, The lack of an appropriate formulation for temozolamide, methotrexate, 6-mercaptopurine and 6-thioguanine is felt as the most annoying lack in the provision of medication to children.
Conclusion
As indicated earlier, dosing in infants dose recommendations is often based on extrapolation from data in older children, which is in most cases is not based on scientific data. Most treatment protocols merely advise either standard dose reductions for all cytostatic drugs or they advise in children below a certain age the use of other parameters (e.g. weight instead of body surface area). The current methods to predict PK and adequate dosing; i.e. modeling/pharmacometrics, give acceptable results for older children. However below the age of 3years the result do need substantial improvement.[362], [363] In this review data on both ontogeny of metabolic pathways and data from PK studies in infants were collected from literature. Major points that become evident were the shifts in activity of metabolic pathways related to ontogeny. Especially the phase I and II enzymes are known for the volatile changes in activity. Renal elimination pathways probably show a more gradual development. In respect to the metabolism of cytostatic drugs two aspects merit special attention. Firstly, generally we do not know if enzymes, which are characteristic for infants and do not come to expression at later ages, are involved in the metabolism of cytostatic drugs. As a result we might be unaware of substantial amounts of either active or inactive metabolites of the parent drug, resulting in either increased or decreased activity and unexpected toxicity. Secondly, a high percentage of administered cytostatic drugs are prodrugs with no or limited cytostatic activity. Decreased activation might, in case the parent drug is not excreted, lead to a prolonged period of exposure to the active drug. The concentration of active compounds is dependent on the activity of the, often immature, elimination mechanisms of these metabolites. In case the parent drug has a delayed activation and the parent compound is excreted in a normal or higher amount, less active drug will be present. Both phenomena influence pharmacodynamics. For cytostatic drugs not in need for activation the differences in metabolic pathways and elimination routes will lead to other (often increased) toxicity (see Table 1). A summary of the literature data on the various enzymes can be found in Table 2. Making assumptions from these data is still difficult; since no data on the use of alternative pathways and alterations in expression and activity of isoforms of the specific enzymes on cytostatic drugs related to infancy are known. For several drugs the consequences of differences in tissue binding, volume of distribution related to another composition of the body and alternative cell entry characteristics in infancy are unknown. For drugs like dactinomycin and bleomycin this might be quite important. Another issue of importance are the differences in handling of cytostatic drugs in various malignancies. Striking differences in metabolic handling can occur as compared to adult forms of the same malignancy. But in the same disease within the pediatric age group differences exist in relation to subtyping based on immunology, cytogenetics and even age. From the heterogeneous data from the various drugs only limited general recommendations can be formulated. In principle for those drugs that might have a lower rate of activation and/or a decay a prolonged exposure is likely. In relation to this phenomenon prolonged intervals between the cytostatic courses could be considered to optimize recovery from hematological and non-hematological side effects of the drug. For drugs were the elimination (both renal and biliary) might be prolonged, decreasing the dosages seems to be logical in order to prevent too high peak values. In case of renal elimination, dose adaptations can be considered using data on actual renal function. Based on these data drugs for which prolongation of interval and a lower dosage should be considered are: cyclophosphamide, ifosfamide, procarbazine, dacarbazine, temozolamide, lomustine, carmustine, vinca alkaloids, taxanes, all topoisomerase inhibitors, all anthracyclines, mitoxantrone, all platinum-based drugs and bleomycin. At least dose reductions should be considered for melphalan, Ara-C, gemcitabine, methotrexate, pemetrexed, 6-mercaptopurin, 6-thioguanin, 5-fluorouracil, fludarabine, cladribine and dactinomycin (see Table 3). For oral busulfan there are adequate recommendations, although due to the high variance dose monitoring and use of the intravenous formulation is preferred. In respect to the age groups within the infant group, the above made recommendations are valid for ages up to the 6months after birth. Later on there will be shifts to PK as seen in older children. However, it is likely that for each cytostatic drug the moment and the speed these shift occur will be different.
Table 2. Major identified ontogenic factors on drug metabolizing enzymes in infants.
| Drug | Fetal expression, silenced or low expression within 1–2years a | Fetal expression at relatively constant level; some postnatal increasea | Substantial increase in the first 1–2yearsa | |||
|---|---|---|---|---|---|---|
| Activation | Degradation | Activation | Degradation | Activation | Degradation | |
| Cyclophosphamide | CYP2C9 | CYP3A5 | CYP2B6 | CYP3A4 | ||
| CYP2C19 | GSTA1 | CYP3A4 | ADH | |||
| ALDH | ||||||
| GST | ||||||
| Ifosfamide | CYP2B6 | CYP3A4 | ||||
| CYP3A4 | ALDH | |||||
| ADH | ||||||
| GST | ||||||
| Procarbazine | CYP2B6 | |||||
| CYP1A | ||||||
| Dacarbazine | CYP1A1 | |||||
| CYP1A2 | ||||||
| CYP2E1 | ||||||
| Temozolamide | ||||||
| Thiotepa | CYP3A4 | |||||
| CYP2B6 | ||||||
| Busulfan | GST | CYP3A4 | ||||
| Vinca alkaloids | CYP3A4 | |||||
| Paclitaxel | CYP2C8 | |||||
| CYP3A4 | ||||||
| Docetaxel | CYP3A5 | CYP3A4 | ||||
| Etoposide | CYP3A5 | CYP3A4 | ||||
| CYP1A1/2 | ||||||
| Topotecan | CYP3A4 | |||||
| Irinotecan | CYP3A4 | |||||
| Doxorubicin /Daunorubicin | CYP2D6 | CYP3A4 | ||||
| Mitoxantrone | CYP3A | |||||
aAccording to Hines 2008 and Mc Carver 2002. |
Table 3. Summary of differences in ADME in infants compared to adults.
| Drug | Absorption | Metabolism | Elimination | ||
|---|---|---|---|---|---|
| Activation | Decay | Renal | Biliary | ||
| Cyclophosphamide | NR | Decreased | Decreased | + | − |
| Ifosfamide | NR | Decreased | Decreased | + | − |
| Procarbazine | ND | Decreased | ND | + | − |
| Dacarbazine | ND | Decreased | ND | + | − |
| Temozolamide | ND (decreased ??) | Normal | Decreased | + | − |
| Thiotepa | NR | – | – | + | − |
| Lomustine/Carmustine | ND | Decreased | Decreased | + | − |
| Chlorambucil | ND | – | Decreased | + | − |
| Busulfan | ND | Decreased | Decreased | + | − |
| Melphalan | NR | ND | ND | + | − |
| Ara-C | NR | Intracellular – tumor cell dependent | Intracellular – tumor cell dependent | + | − |
| Gemcitabine | NR | Intracellular – tumor cell dependent | Intracellular – tumor cell dependent | + | − |
| Methotrexate (oral) | ND | – | ND | + | − |
| Methotrexate (intravenous) | NR | – | ND | + | − |
| Pemetrexed | NR | ||||
| 6-mercaptopurin | ND | ND | TPMT dependent | + | − |
| 6-thioguanin | ND | ND | TPMT | − | ± |
| 5-fluorouracil | NR | ND | ND | − | + |
| Fludarabine | NR | Intracellular – tumor cell dependent | Intracellular – tumor cell dependent | + | − |
| Cladribine | NR | Intracellular – tumor cell dependent | Intracellular – tumor cell dependent | + | − |
| Vinca alkaloids | NR | – | Decreased | − | + |
| Taxanes | NR | – | Decreased | − | + |
| Etoposide | NR | Decreased | Decreased | ± | + |
| Teniposide | NR | Decreased | Decreased | ± | + |
| Irinotecan | NR | Decreased | Decreased | ± | + |
| Doxorubicin/Daunorubicin | NR | – | Decreased | − | + |
| Epirubicin | NR | – | Decreased | − | + |
| Mitoxantrone | NR | – | Decreased | − | + |
| Dactinomycin | NR | – | – | + | + |
| Bleomycin | NR | Decreased ? | ND | + | − |
| Cisplatin | NR | – | Decreased | + | − |
| Carboplatin | NR | – | Decreased | + | − |
| Oxaliplatin | NR | ? | ? | + | − |
The summarized data as collected from the literature clearly illustrate that the administration of cytostatic drugs in infants is currently often not based on PK data. As such the statement that each infant treated with cytostatic medication is eligible for pharmacokinetic determinations is valid. As a consequence researchers should publish their results. Compiling these data in a global database would enable evidence-based drug therapy in infants with malignancies, resulting in a more effective treatment and less toxic treatment in this vulnerable population.
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PII: S0305-7372(11)00059-4
doi:10.1016/j.ctrv.2011.03.005
© 2011 Elsevier Ltd. All rights reserved.
