The role of pharmacokinetic and pharmacodynamic studies in the planning of protocols for the treatment of childhood cancer☆
Abstract
The chemosensitive nature of many childhood cancers means that chemotherapy has a greater role in therapy than in adult practice. However, the present methods, schedules of administration and combinations have often been derived form historical precedent rather than from pharmacological knowledge. For many drugs, paediatric phase I and II studies have never been performed and reliance on adult studies will be inadequate as children may show differences in drug disposition or susceptibility to toxicity. In this review, we examine pharmacokinetic and pharmacodynamic studies as they relate to the treatment of a 'model' childhood cancer in the UK: acute lymphoblastic leukaemia (ALL). Each of the drugs used is examined in the light of pharmacological evidence. For the drugs L-asparaginase, methotrexate, cytarabine and the thiopurines, this evidence suggests that the current use of these drugs is not optimal and that significant improvements in cure for ALL might be achieved by pharmacologically guiding their use. We highlight an important recent study demonstrating a 10% increase in long-term survival in childhood ALL by the use of pharmacologically guided dosing compared to standard (by body surface area) dosing. Since significant improvements in survival may depend upon such effective use, we suggest that pharmacological studies become an integral part of phase II and phase III trials of treatments for childhood cancer.
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