1618 - In Vitro Drug-Drug Interaction Studies with the Antiemetic Drug Netupitant and its Major Metabolites M1 and M2, Involving Several Human Cytochrome P450 Isoenzymes

Abstract

ABSTRACT Introduction Nausea and emesis are significant adverse events of chemotherapy. Substance P plays a major role in the emetic process especially in the delayed emesis occurring 24h after treatment and beyond. Antagonism of substance P effect at the neurokinin 1 (NK1) receptor level is a validated target in showing a broad antiemetic activity in animal models of emesis and also in humans. Within the new NK1 antagonists in clinical trials, Netupitant (Netu) has been characterized as an antiemetic in vitro and in vivo in various pharmacological experiments against emesis induced by chemotherapeutics. In vitro studies have shown that the CYP3A4 isoenzyme is the major enzyme involved in the oxidative metabolism of Netu. Methods The in vitro inhibition potential of Netu and its major metabolites M1 and M2 has been studied for the human cytochrome P450 isoenzymes CYP1A2, 2C9, 2C19, 2D6 and 3A4 utilizing human liver microsomes and isoform selective substrates. Results Netu inhibited the CYP3A4-dependent metabolism of the two isoform selective probe-substrates midazolam and testosterone with estimated IC50 (±S.E.) values of 5.9 ± 1 and 1.7 ± 0.2 µM, respectively. For the hydroxylation of diclofenac, catalyzed by CYP2C9, IC50 (±S.E.) of 18.0 ± 6 and 22.6 ± 3 µM were calculated in two different experiments, utilizing both the free base, and the Netu hydrochloride as inhibitors. Netu showed no significant inhibition potential for CYP1A2, 2C19 and 2D6 (IC50s >100 µM). Conclusions Significant metabolic drug-drug interactions in human are not anticipated for compounds metabolized mainly by CYP1A2, 2C19 and 2D6 and are very unlikely for CYP2C9 metabolized drugs based on the expected human plasma concentration of Netu in the low μmolar range. However, metabolic drug-drug interactions are possible for co-medicated drugs metabolized mainly by CYP3A4, based on the high in vitro affinity of Netu for this isoenzyme, as tested with testosterone and midazolam (app Ki ∼ 1.1 to 2.2 µM) and for the inhibition potential of the metabolites M1 and M2 similar to the parent compound. The in vivo CYP3A4 interaction has been studied in appropriate designed clinical interaction studies. Disclosure C. Giuliano: Helsinn healthcare employee, E. Lovati: Helsinn Healthcare employee, C. Funk: Roche employee, M. Potthast: Roche employee, C. Pietra: Helsinn employee.