Pharmacological exposure optimisation of anticancer agents during clinical development

Abstract

In recent years, drug development in oncology switched focus from conventional cytotoxic drugs to targeted therapies. Despite this change in focus, dose selection of anticancer drugs in early drug development is still often solely based on toxicity. Dose selection could be further improved by using both exposure-efficacy and exposure-toxicity relationships for decision making. Therefore, a thorough understanding of these relationships is essential. This thesis aimed to contribute to the paradigm switch of dose selection in oncology drug development by investigating novel methodologies for dose optimisation and dose extrapolation. The first finding was that microdoses (max. 100 µg) and microtracers (isotopically labelled drugs dosed at a microdose) can efficiently be used for the characterisation of pharmacokinetic processes in early drug development. Data obtained with these studies provide essential information on dose selection for subsequent dose-finding Phase I clinical trials, and therefore, these type of studies should become an integral part of drug development for new anticancer drugs. The second finding was that relatively simple bioanalytical methods are capable of quantifying drug concentrations in complex matrices. Moreover, novel ultrasensitive LC-MS/MS bioanalytical methods enable pharmacokinetic studies which were not possible before (such as microdose and microtracer studies) which were used to make important contributions to dose optimisation for instance in special populations like paediatrics, where only small volumes of the biomatrix can be obtained. The last finding was that pharmacometrics are a powerful tool for the characterisation and extrapolation of drug exposure and exposure-response relationships. These models were used to inform dose selection for future clinical studies. Lastly, pharmacometrics can optimise clinical study designs and thereby reduce the patient burden of these studies.