Abstract C133: Effect of casopitant, a novel neurokinin-1 receptor antagonist, on the pharmacokinetics (PK) of the oral contraceptive pill (OCP)

Abstract

Abstract Background: Clinical studies suggest that casopitant, a novel neurokinin-1 receptor antagonist in development for prevention of postoperative and chemotherapy-induced nausea and vomiting (PONV and CINV, respectively), is a mild to moderate inhibitor of CYP3A4. However, in cultured human hepatocytes, induction of CYP3A4 and UGT enzymes also has been observed. Since casopitant is intended for use in women receiving moderately emetogenic chemotherapy for breast cancer, the current studies evaluated the pharmacokinetics (PK) of a combined monophasic oral contraceptive pill (OCP) coadministered with repeat-dose casopitant. Methods: Healthy female subjects of non-childbearing or of childbearing potential taking OCP were enrolled. Study 1 (N=11) was a randomized, double-blind, placebo-controlled, repeat-dose, crossover study. OCP containing 30 µg ethinylestradiol (ETE) and 150 µg levonorgestrel (LEV) was administered for 2 complete menstrual cycles (21 days + 7-day washout), plus oral placebo or 60 mg casopitant on days 1–14 of each cycle. Study 2 (N=61) was a single-blind, placebo-controlled, repeat-dose, single-sequence study. OCP was administered for 2 complete cycles as above with oral casopitant (30 mg or 120 mg) or placebo administered for cycles 1 and 2, respectively. Casopitant or placebo was administered for 28 consecutive days, beginning 7 days before OCP administration. The geometric least squares mean ratios and 90% confidence intervals (CI) for ETE and LEV AUC and Cmax were calculated to compare OCP + casopitant vs OCP + placebo. Results: In study 1, ETE AUC(0−) and Cmax were decreased on average by 16% and 17%, respectively, when the OCP was coadministered with 60 mg casopitant vs placebo. Geometric mean LEV AUC(0−) increased 4%, and Cmax decreased 17%. In study 2, for ETE, OCP + casopitant decreased AUC(0−) on average by 15% and 40%, and Cmax by 24% and 32% with 30 mg and 120 mg, respectively. For LEV, the largest mean change in exposure was a 13% decrease in Cmax with 120 mg casopitant given daily for 14 days. Coadministration of casopitant with the combined OCP was well tolerated in both studies. Conclusions: Continuous coadministration of casopitant for 14 or 28 days with a combined monophasic OCP resulted in only a small change in LEV exposure, but a dose-dependent reduction in ETE exposure that may reduce the efficacy of hormonal contraceptives. The effect of a single oral dose of casopitant on hormonal contraceptives has not been studied. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C133.