Preclinical and clinical pharmacology of oral anticancer drugs

Abstract

Nowadays, more than 25% of all anticancer drugs are developed as oral formulations. Oral administration of drugs has several advantages over intravenous (i.v.) administration. It will on average be more convenient for patients, because they can take oral medication themselves, there is no need for frequent hospitalization, and the discomfort of an injection or infusion and risk for injection or infusion associated adverse events is absent. New oral anticancer drugs are developed to have favourable pharmacological profiles and negligible affinity for drug efflux transporters and metabolic degradation enzymes. However, in clinical studies limited oral bioavailability, high inter-individual variability in pharmacokinetics, enzyme induction/inhibition, genetic polymorphisms and unwanted drug-drug interactions have been observed with new oral anticancer drugs. The studies described in this thesis show that ATP-Binding Cassette (ABC) drug transporters, solute carrier (SLC) transporters, metabolic cytochrome P450 enzymes and the drug formulation all can largely affect the (pre)clinical pharmacology of orally applied anticancer drugs. This concerns drugs primarily developed for the oral route, such as most tyrosine kinase inhibitors, and drugs primarily developed for i.v. administration, but now under review for oral application, such as the taxanes docetaxel and paclitaxel. Our preclinical results demonstrate the importance of comprehensive absorption, distribution, metabolism and elimination (ADME) studies with new oral anticancer drugs to better estimate the pharmacological profile in the clinic. Although it is a useful way to pre-screen new test drugs in vitro with affinity for well known ABC transporters and CYP enzyme substrates or inhibitors, it is recommended to enlarge this screen with SLC transporters. By using sophisticated preclinical models (in vitro drug transporter/biotransformation assays and drug transporter/CYP enzyme knockout mice models), the influence of drug transporters and CYP enzymes in the ADME of oral drugs and drug-drug interactions in the clinic can be better predicted. That preclinically designed concepts could successfully be translated to the clinic is shown in this thesis for oral docetaxel in combination with ritonavir. This is one of the first clinical examples that concomitant use of transporter and/or CYP enzyme inhibitors with oral anticancer drugs is an effective and safe strategy that is at least as effective as standard i.v. therapy. Besides the transport proteins and CYP enzymes, the type of oral formulation can be important in order to deliver a certain oral drug with an adequate oral bioavailability and low inter-individual variability. Slow progress has been made over the last years and several new drug carrier systems, such as liposomes, polymeric micelles and (albumin) nanoparticles, are in development. The communication between preclinical and clinical research is of high importance to better understand the pharmacology of drugs in humans. This can probably prevent termination of drug development at later stage and accelerate the development of new oral drugs