Pharmacological dose optimization in children with cancer

Abstract

Dosing of (chemotherapeutic) agents in pediatric patients with cancer can be challenging. An optimal exposure to chemotherapeutic and anti-emetic agents is needed, either to be effective, and on the other hand, to minimize toxicity. Developmental changes can influence drug absorption, distribution, metabolism and excretion (ADME), and should, therefore, structurally be considered in pediatric dosing. This thesis focused on age-related differences in pharmacokinetics (PK) and pharmacological dose optimization of chemotherapeutic and anti-emetic agents in (young) children with cancer. Several PK modelling techniques were used to study the PK of five chemotherapeutic (carboplatin, cisplatin, clofarabine, doxorubicin and vincristine) and two anti-emetic (aprepitant and dexamethasone) agents in children. Practical dosing recommendations for these agents were formulated. Moreover, this thesis points out that, also in pediatric oncology, children are not small adults, so clinical pharmacological knowledge should be included in clinical practice to optimise the dose of (chemotherapeutic) agents. Collection of (real life) data from young children is possible and can be used for in depth PK modelling, which is essential to translate PK data into practical (dose) recommendations. A recommended work-flow for studying the PK of marketed drugs in neonates and infants was proposed, which forms the basis for further optimization of dosing guidelines of (chemotherapeutic) agents in pediatric oncology.