A single-dose PK study of onapristone including the effect of food on absorption

Abstract

Purpose

Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability.

Methods

This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods.

Results

Onapristone plasma t1/2 (mean ± SD) was 4.36 ± 0.81 h for the fasted state and 3.76 ± 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0–∞ of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23-day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose.

Conclusion

The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food.

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Acknowledgments

The authors thank Mr. Matthew F. Reid, Bexon Clinical Consulting for medical writing. Funder—Arno Therapeutics Inc., Flemington, NJ, USA.

Conflict of interest

K. Rezai, A. Bexon, E. Gilles and F. Lokiec are consultants for Arno Therapeutics, the developer of onapristone; D. Chassard, C. Denot, H. L. Ramos and A. Patat are employees of Biotrial, the CRO which performed the study; Stefan Proniuk, A. Zukiwski are employees of Arno Therapeutics.

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Correspondence to Keyvan Rezai.

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Rezai, K., Chassard, D., Denot, C. et al. A single-dose PK study of onapristone including the effect of food on absorption. Cancer Chemother Pharmacol 76, 171–177 (2015). https://doi.org/10.1007/s00280-015-2754-3

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Keywords

  • Onapristone
  • Pharmacokinetic
  • Food
  • Safety
  • Tolerability