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

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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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References

  1. Allan GF, Tsai SY, Tsai M-J, O’Malley BW (1992) Ligand-dependent conformational changes in the progesterone receptor are necessary for events that follow DNA binding. Proc Natl Acad Sci 89(24):11750–11754

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Clemm DL, Sherman L, Boonyaratanakornkit V, Schrader WT, Weigel NL, Edwards DP (2000) Differential hormone-dependent phosphorylation of progesterone receptor A and B forms revealed by a phosphoserine site-specific monoclonal antibody. Mol Endocrinol 14(1):52–65

    Article  CAS  PubMed  Google Scholar 

  3. Graham JD, Hanson AR, Croft AJ, Fox AH, Clarke CL (2009) Nuclear matrix binding is critical for progesterone receptor movement into nuclear foci. FASEB J 23(2):546–556

    Article  CAS  PubMed  Google Scholar 

  4. Mote P, Clarke C (2000) Relative expression of progesterone receptors A and B in premalignant and invasive breast lesions. Breast Cancer Res 2(Suppl 1):21–22

    Article  Google Scholar 

  5. Arnett-Mansfield RL, DeFazio A, Mote PA, Clarke CL (2004) Subnuclear distribution of progesterone receptors A and B in normal and malignant endometrium. J Clin Endocrinol Metab 89(3):1429–1442

    Article  CAS  PubMed  Google Scholar 

  6. Scarpin KM, Graham JD, Mote PA, Clarke CL (2009) Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nucl Recept Signal 7:1–13

    Google Scholar 

  7. Graham D, Bosq J, Caillaud J-M, Powell MA, Leblanc E, Fujiwara K, Herzog TJ, Monk BJ, Clarke C, Zukiwski AA, Gilles EM, Coleman RL (2013) Determination of the activated form of the progesterone receptor (PR) in endometrial cancer (EC). In: Proceedings of the annual meeting of the American society of clinical oncology

  8. Mote P, Bartow S, Tran N, Clarke C (2002) Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 72(2):163–172

    Article  CAS  PubMed  Google Scholar 

  9. Nishino T, Ishibashi K, Hirtreiter C, Nishino Y (2009) The prostate growth stimulation by progesterone is due to androgenic products and progesterone receptor-mediated mechanisms. Pharmazie 64(9):587–589

    CAS  PubMed  Google Scholar 

  10. Rudereanu D, Vering A, Stegmüller M, Bender HG (1992) Wirkung des Progesteronantagonisten Onapristone in einem xenotransplantierten Endometriumkarzinom. In: Gynakologie und Geburtshilfe. Onkologie- Grundlagen und Chemotherapie, pp 1065–1067

  11. Jonat W, Giurescu M, Robertson JF (2002) The clinical efficacy of progesterone antagonists in breast cancer. In: Robertson J, Nicholson R, Hayes D (eds) Endocrine therapy of breast cancer. Martin Dunitz Ltd, London, pp 117–124

    Google Scholar 

  12. Robertson J, Willsher P, Winterbottom L, Blamey R, Thorpe S (1999) Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer. Eur J Cancer 35(2):214–218

    Article  CAS  PubMed  Google Scholar 

  13. Zurth C, Kagels F (1990) Determination of onapristone and its N-desmethyl metabolite in human plasma or serum by high-performance liquid chromatography. J Chromatogr 115–123

  14. Jang GR, Benet LZ (1998) Antiprogestin-mediated inactivation of cytochrome P450 3A4. Pharmacology 56(3):150–157

    Article  CAS  PubMed  Google Scholar 

  15. Cameron ST, Critchley HO, Buckley CH, Chard T, Kelly RW, Baird DT (1996) The effects of post-ovulatory administration of onapristone on the development of a secretory endometrium. Hum Reprod 11(1):40–49

    Article  CAS  PubMed  Google Scholar 

  16. Jang GR, Benet LZ (1997) Antiprogestin pharmacodynamics, pharmacokinetics, and metabolism: implications for their long-term use. J Pharmacokinet Biopharm 25(6):647–672

    Article  CAS  PubMed  Google Scholar 

  17. Cottu PH, Varga A, Giacchetti S, Eric Leblanc, Espie M, Gazzah A, Dieras V, Lhomme C, Lokiec FM, Rezai K, Bexon AS, Erard M. Gilles, Bisaha J, Zukiwski AA, Bonneterre J (2014) A randomized, parallel-dose phase 1 study of onapristone (ONA) in patients (pts) with progesterone receptor (PR)-expressing cancers. J Clin Oncol 32 (5 s):abstr TPS2643

  18. Mateo J, Rodrigues DN, Lopez RP, Flohr P, Riisnaes R, Lokiec FM, Zukiwski AA, Proniuk S, Bexon AS, Paquin A, Bisaha J, Tunariu N, De Bono JS, Attard G (2014) A phase 1-2 study of the type I progesterone receptor (PR) antagonist onapristone (ONA) in patients (pts) with advanced castration resistant prostate cancer (CRPC). J Clin Oncol 32 (5 s):abstr TPS5097

  19. Zytiga (abiraterone acetate) summary of product characteristics (last revised June 2014). Janssen-Cilag Limited Bucks UK. http://www.medicines.org.uk/emc/medicine/24976/SPC/Zytiga+250+mg+tablets/. Accessed 6 July 2014

  20. Megace (megestrol acetate) summary of product characteristics (last revised April 2014). Swedish Orphan Biovitrum Limited Cambs UK. http://www.medicines.org.uk/emc/medicine/346/SPC/Megace+160+mg+Tablets/. Accessed 6 July 2014

  21. European Medicines Agency (2012) Committee for human medicinal products for human use (CHMP): guideline on the Investigation of Drug Interactions. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf. Accessed 6 July 2014

  22. Food and Drug Administration (2002) Guidance for industry: food-effect bioavailability and fed bioequivalence studies, US Department of Health and Human Services. http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126833.pdf. Accessed 6 July 2014

  23. European Medicines Agency (2011) Committee for human medicinal products for human use (CHMP): guideline on bioanalytical method validation. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf. Accessed 6 July 2014

  24. Food and Drug Administration (2001) Guidance for industry: bioanalytical method validation. http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf. Accessed 6 July 2014

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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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Authors and Affiliations

  1. Radiopharmacology Department, Institut Curie, Saint Cloud, France

    Keyvan Rezai & François Lokiec

  2. Biotrial Paris, Stell Hospital, Paris, France

    Didier Chassard, Caroline Denot, Haydeé L. Ramos & Alain Patat

  3. Arno Therapeutics Inc., Flemington, NJ, USA

    Stefan Proniuk & Alexander Zukiwski

  4. Invivis Pharmaceuticals, Bridgewater, NJ, USA

    Erard Gilles

  5. Bexon Clinical Consulting, Montclair, NJ, USA

    Alice Bexon

Authors
  1. Keyvan Rezai
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  2. Didier Chassard
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  3. Caroline Denot
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  4. Stefan Proniuk
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  5. Alexander Zukiwski
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  6. Erard Gilles
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  7. Haydeé L. Ramos
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  8. Alain Patat
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  9. Alice Bexon
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  10. François Lokiec
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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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  • DOI: https://doi.org/10.1007/s00280-015-2754-3

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