Effects of rolapitant administered orally on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects

• Published in: Supportive care in cancer Vol. 27; no. 3; pp. 819 - 827
• Main Authors: Wang, Jing, Zhang, Zhi-Yi, Lu, Sharon, Powers, Dan, Kansra, Vikram, Wang, Xiaodong
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2019; Springer Nature B.V
• Subjects: Administration, Oral; Adolescent; Adult; Antiemetics; Antiemetics - pharmacology; Antiretroviral drugs; Benzoxazines - pharmacokinetics; Carbamates - pharmacokinetics; Clinical significance; Cytochrome P-450 CYP2B6 - drug effects; Cytochrome P-450 CYP2C19 - drug effects; Cytochrome P-450 CYP2C8 - drug effects; Cytochrome P-450 CYP2C9 - drug effects; Cytochrome P-450 CYP2D6 - drug effects; Dextromethorphan - pharmacokinetics; Drug Combinations; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Molecular Probes - pharmacokinetics; Nausea; Neurokinin-1 Receptor Antagonists - administration & dosage; Neurokinin-1 Receptor Antagonists - pharmacology; Nursing; Nursing Research; Omeprazole - pharmacokinetics; Oncology; Original; Original Article; Pain Medicine; Pharmacokinetics; Piperidines - pharmacokinetics; Rehabilitation Medicine; Spiro Compounds - pharmacology; Tolbutamide - pharmacokinetics; Young Adult; Antiemetics; Rolapitant; Neurokinin-1 receptor antagonist; Drug interactions; Cytochrome P450
• ISSN: 0941-4355; 1433-7339; 1433-7339
• DOI: 10.1007/s00520-018-4331-x

Purpose Rolapitant is a neurokinin-1 receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed chemotherapy-induced nausea and vomiting. We evaluated the effects of rolapitant oral on the pharmacokinetics of probe substrates for cytochrome P450 (CYP) 2D6 (dextromethorphan), 2C9 (tolbutamide), 2C19 (omeprazole), 2B6 (efavirenz), and 2C8 (repaglinide) in healthy subjects. Methods This open-label, multipart, randomized, phase 1 study assessed cohorts of 20–26 healthy subjects administered dextromethorphan, tolbutamide plus omeprazole, efavirenz, or repaglinide with and without single, oral doses of rolapitant. Maximum plasma analyte concentrations ( C max ) and area under the plasma analyte concentration–time curves (AUC) were estimated using noncompartmental analysis, and geometric mean ratios (GMRs) and 90% confidence intervals for the ratios of test (rolapitant plus probe substrate) to reference (probe substrate alone) treatment were calculated. Results Rolapitant significantly increased the systemic exposure of dextromethorphan in terms of C max and AUC 0–inf by 2.2- to 3.3-fold as observed in GMRs on days 7 and 14. Rolapitant did not affect systemic exposure of tolbutamide, and minor excursions outside of the 80–125% no effect limits were detected for omeprazole, efavirenz, and repaglinide. Conclusions Inhibition of dextromethorphan by a single oral dose of rolapitant 180 mg is clinically significant and can last at least 7 days. No clinically significant interaction was observed between rolapitant and substrates of CYP2C9, CYP2C19, CYP2B6, or CYP2C8. CYP2D6 substrate drugs with a narrow therapeutic index may require monitoring for adverse reactions if given concomitantly with rolapitant.