PhD defence: Relevance of pharmacological boosters in the disposition of oral anticancer drugs

Drug response and toxicity, as well as drug-drug interactions, are in part determined by the influence of drug transporters and drug-metabolizing enzymes. The ATP-binding cassette (ABC) drug efflux transporters and the organic anion transporting polypeptide (OATP) drug uptake transporters are transmembrane transporters expressed in pharmacologically essential organs, such as the liver, small intestine and the blood-brain-barrier. Drug-metabolizing enzymes such as Cytochrome P450 (CYP) 3A and carboxylesterase (CES) 1 could also influence the pharmacokinetics of their substrate drugs. All these proteins can affect the absorption, distribution, elimination and toxicity of many drugs. This thesis describes several pharmacological studies with (oral) anticancer drugs in knockout and transgenic mouse models. Moreover, we used pharmacological inhibitors to modulate these systems.

One extensively studied compound in this dissertation is cabazitaxel, a semi-synthetic taxane, used in prostate cancer. In the development of oral taxane formulations, the pharmacological booster ritonavir, a potent CYP3A inhibitor, plays an important role, because taxanes are extensively metabolized by CYP3A. Coadministration of ritonavir enhanced the systemic exposure of cabazitaxel in the mouse models. Furthermore, we studied the influence of ABC and OATP transporters and the drug-metabolizing enzymes CYP3A and CES1 on the pharmacokinetics and tissue disposition of the KRASG12C inhibitors sotorasib and adagrasib, and the SYK inhibitors entospletinib and lanraplenib. In these studies, we also successfully applied the pharmacological booster elacridar, a dual ABCB1/ABCG2 inhibitor, to increase the brain penetration of these drugs. Usage of boosters also allows for less frequent dosing of the substrate drug(s), potentially leading to improved patient adherence.