Pharmacokinetic (Pk) Food Effect Study Of Immediate-Release Onapristone And Its Primary Metabolite (M1) In Healthy Female Subjects: Implications For Design Of A New Formulation

Abstract Introduction: Onapristone is an antiprogestin with demonstrated clinical activity in breast cancer, reported to have a t1/2 between 2 and 4 hours. Drugs such as megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect (≥10 x Cmax variation; ≥5 x AUC variation). A study was conducted to determine the best formulation of onapristone to minimize this variability. Methods: The aim of this study was to determine the pharmacokinetic profile of onapristone and mono-desmethyl onapristone (M1), with and without food. Using a two-period, two-sequence, random assignment cross-over design, twelve healthy female subjects were given 10 mg of an oral immediate release formulation of onapristone either after an overnight fast, or within 30 minutes after a high-fat high-calorie meal, with a 2 week washout between dosing periods. PK sampling was performed following each oral administration at: 0, 15, 30, 45 and 60 minutes, 2, 4, 6, 8, 12, 16 and 24 hours (h). Parameters were calculated using the linear trapezoidal method. Population PK modeling was conducted using the nonlinear mixed effect model. Results: Onapristone plasma t1/2 (mean ± SD) was 4.36 ±0.81 h for the fasted and 3.76 ±0.36 h for the fed state. The absorption phase appeared linear. Onapristone tmax was delayed from 1 to 4 h after food intake. A small effect on the single dose onapristone pharmacokinetic profile was also observed, with a slightly decreased mean Cmax (18%) and increased AUC0-last (11%). Mean population CL of onapristone was 5.02 ±0.67 L/h and 6.63 ±0.87 L/h for fasted and fed states respectively. There was no food effect on M1 exposure but a decrease in M1 plasma peaks (∼35%) after food intake. The onapristone time-concentration curve was adequately described by a 2-compartment open model with linear elimination using a population PK approach. A significant food effect (p<0.0001) was observed on CL of onapristone but not M1. Modeling confirmed that food increased onapristone AUC. One subject aged 27 experienced a 23-day delay in menses after one 10mg onapristone dose and 1 subject experienced transient G2 liver enzyme elevation 3 weeks post-dose. Conclusion: Clinically meaningful Cmax can be reached with a 10 mg onapristone dose. The results are consistent with prior observations, indicating that food delayed absorption and increased AUC when taken concomitantly. Food effect is minimal compared to other drugs in class, but onapristone should preferably be administered 2 hours before or 1 hour after meals. This food effect is unlikely to have clinical consequences. As absorption is linear, a sustained release formulation would probably reduce Cmax by ∼25% while not substantially modifying AUC. Given the estimated t1/2 of 2-4 hours, adequate concentrations should be maintained with twice a day dosing. Citation Format: Keyvan Rezai, Stefan Proniuk, Alex Zukiwski, Erard Gilles, Didier Chassard, Caroline Denot, Haydee L. Ramos, Alice S. Bexon, François Lokiec. Pharmacokinetic (PK) food effect study of immediate-release onapristone and its primary metabolite (M1) in healthy female subjects: implications for design of a new formulation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4636. doi:10.1158/1538-7445.AM2014-4636