Hoge doseringen van cyclofosfamide, thiotepa en carboplatine: De relatie tussen toxiciteit en farmacokinetiek

High-dose chemotherapy with autologous peripheral blood progenitor cell transplantation is currently under investigation for the treatment of several solid tumors. The combination cyclophosphamide + thiotepa + carboplatin (CTC) is one of the most frequently used regimens. With stem cell transplantation, bone marrow toxicity is no longer dose-limiting but other severe and sometimes life-threatening toxicities may occur. A wide interpatient variability in toxicity is observed, which may be due to variability in the pharmacokinetics of the antineoplastic agents and their metabolites. Identification of relationships between toxicity and the pharmacokinetics in the CTC regimen was the subject of a research project. Several relations have been identified in this project. Population pharmacokinetic models have been developed which enable the estimation of individual pharmacokinetic parameters based on a few blood samples. Furthermore, relevant pharmacokinetic targets were defined. Based on these parameters doses could individually be adapted. Retrospective analyses have shown that these dosing methods could substantially reduce the variability in the pharmacokinetics of thiotepa and carboplatin. In a prospective pilot study, the feasibility of these methods in clinical practice was demonstrated. Prospective, comparative studies will be necessary to demonstrate whether pharmacokinetically guided dosing of the agents in the CTC regimen will reduce toxicity without comprising toxicity.