Abstract C62: Effects of rolapitant on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects
Authors: Wang Xiaodong , Zhang Zhi-Yi , Wang Jing , Lu Sharon , Arora Sujata , Hughes Lorraine , Christensen Jennifer , Kansra Vikram 
Published: May 2016

Introduction: Rolapitant is a selective and long acting NK-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting (CINV). In vitro results indicated rolapitant mildly inhibited cytochrome P450 (CYP450) enzymes (2D6/2C9/2C19/2B6/2C8) at high concentrations (IC50s &gt; 7 μM). The major metabolite SCH720881 did not inhibit these CYP enzymes.

This study aimed to 1) evaluate the effects of rolapitant on the pharmacokinetics (PK) of CYP probe substrates (dextromethorphan [DET] for CYP2D6, tolbutamide [TOL] for CYP2C9, omeprazole [OMP] for CYP2C19, efavirenz [EFA] for CYP2B6 and repaglinide [REP] for CYP2C8), and 2) evaluate the safety and tolerability of rolapitant co-administered with these substrates in healthy subjects.

Methods: This was an open-label, multi-part drug-drug interaction study in cohorts of 20 to 26 healthy subjects of orally-administered CYP probe substrates (Part-A: 30 mg DET; Part-B: 500 mg TOL plus 40 mg OMP; Part-C: 600 mg EFA; Part-D: 0.25 mg REP) in the absence and presence of single oral dose 180 mg rolapitant. Blood samples for determination of plasma concentration of CYP substrates and relevant metabolites were collected during 3 dosing periods in each part: 1) Period-1: CYP probe substrate alone as baseline; 2) Period-2: CYP probe substrate plus rolapitant concomitantly after a washout of probe given in Period 1 to evaluate the potential impact of rolapitant on probe substrate; and 3) Period-3: CYP probe substrate alone 7 days after the concomitant dose in Period-2 (approximating the peak time of metabolite SCH720881) to evaluate the impact of metabolite/rolapitant on probe substrate.

Results: Rolapitant inhibited CYP2D6 following concomitant dose (Period-2) and 7 days after concomitant dose (Period-3), resulting in 2.2- to 3.3-fold higher exposure (Cmax and AUC) of DET. Rolapitant did not inhibit CYP2C9 following exposure to TOL. The exposure (Cmax & AUC) of CYP2C19 substrate OMP was minimally increased by rolapitant (1.1- to1.4-fold) and is unlikely to be clinically relevant. Rolapitant did not inhibit CYP2B6 or result in clinically relevant changes in exposure of EFA. Rolapitant did not inhibit CYP2C8 or result in clinically relevant changes in exposure of REP. There were no noteworthy adverse events or laboratory findings in any part of the study.

Conclusions: Rolapitant was well-tolerated when co-administered with CYP probe substrates. Co-administration of rolapitant increased the exposure of DET. The inhibition of CYP2D6 can last at least 7 days following single dose of rolapitant. No clinically significant interaction was observed between rolapitant and substrates of CYP2C9, CYP2C19, CYP2B6 or CYP2C8; therefore no dosing adjustment is necessary for drugs which are metabolized by these CYPs.

Citation Format: Xiaodong Wang, Zhi-Yi Zhang, Jing Wang, Sharon Lu, Sujata Arora, Lorraine Hughes, Jennifer Christensen, Vikram Kansra. Effects of rolapitant on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C62.