Relevance of pharmacological boosters in the disposition of oral anticancer drugs: Mouse models

Abstract

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 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 have broad substrate specificities, and can therefore variously affect the (net) absorption, distribution, elimination and toxicity of many drugs. Furthermore, their activities are susceptible to genetic polymorphisms in their encoding genes and to variable tumor-specific expression, resulting in inter- and intra-individual variations in drug response. 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. In this dissertation we extensively studied cabazitaxel, a semi-synthetic taxane used in prostate cancer. Currently, cabazitaxel is administered as a one-hour intravenous infusion every three weeks in combination with prednisolone, but an oral application would potentially be more favorable. 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. Ritonavir itself is also primarily metabolized by CYP3A, and to a lesser extent by CYP2D6. Probably there is auto-inhibition and auto-induction of its metabolism, mainly by (short-term) inactivation of CYP3A and (more long-term) raising of CYP3A levels by gene induction. Coadministration of ritonavir enhanced the systemic exposure of cabazitaxel in the mouse models. Coadministration of the dual ABCB1/ABCG2 inhibitor elacridar to ritonavir-boosted oral cabazitaxel further enhanced cabazitaxel tissue disposition without affecting the plasma exposure. Moreover, the data suggest that the active metabolites DM1, DM2 and docetaxel are also substrates for ABCB1 to various extents. Ritonavir itself was also a potent in vivo substrate for the Abcb1 efflux transporter. The uptake of (oral) cabazitaxel was not affected by the OATP transporters. Overall, these results look promising for the oral application of cabazitaxel and are a good starting point for the set-up of a clinical study. Furthermore, we studied the influence of the ABC and OATP transporters and CYP3A and CES1 on the pharmacokinetics and tissue disposition of the KRASG12C inhibitors sotorasib and adagrasib, and the SYK inhibitors entospletinib and lanraplenib. The pharmacokinetics of sotorasib and adagrasib were restricted by CYP3A and ABCB1, whereas the plasma exposure of adagrasib was strongly reduced in Ces1-/- mice due to binding of adagrasib to plasma Ces1c in mice. The plasma exposure of entospletinib and lanraplenib was not affected by Abcb1 or Abcg2, in contrast to their brain penetration, which was highly limited by these transporters. Therefore, we also successfully applied the pharmacological booster elacridar in these studies to increase the brain penetration of these KRASG12C and SYK inhibitors. Usage of boosters might also allow for less frequent dosing of the substrate drug(s), potentially leading to improved patient adherence and reduced cost.