Skip to main content

Pharmacokinetics and bioequivalence of generic and branded abiraterone acetate tablet: a single-dose, open-label, and replicate designed study in healthy Chinese male volunteers

Abstract

Purpose

Abiraterone acetate is a highly variable drug and has been approved for the treatment of patients with metastatic castration-resistant prostate cancer in many countries. This study was conducted to compare the pharmacokinetic profile between the test product (abiraterone acetate tablet) and reference product ZYTIGA® (250 mg) mainly.

Methods

To overcome the high intra-subject variability of abiraterone, a two-sequence and four-period crossover study was designed to assess bioequivalence between the two products in 32 healthy male Chinese subjects under fasting conditions. The plasma concentration of abiraterone was analyzed by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters.

Results

The point estimate of geometric mean ratios with 90% confidence interval (CI) of maximum observed concentration (Cmax) and the area under the concentration–time curve (AUC0t) for abiraterone in the test and reference products were 100.19% (90% CI 87.05–115.32%) and 105.99% (90% CI 96.34–116.62%), respectively, and were both within the range of 80.00–125.00%. The 95% confidence upper limit bound for \({({\bar {Y}_{\text{T}}} - {\overline {Y} _{\text{R}}})^{\text{2}}}~ - ~\theta S_{{{\text{WR}}}}^{{\text{2}}}{\text{ }}\) was − 0.1079 for Cmax and was − 0.0515 for AUC0t.

Conclusions

Bioequivalence was demonstrated between the two abiraterone acetate products. The study also confirmed high intra-subject variability, for abiraterone: coefficient of variation (CV, %) of Cmax values for the test and reference products were 40.33% and 46.58%, while for AUC0t were 24.02% and 34.16%, respectively.

Trial registration


http://www.chinadrugtrials.org.cn/: CTR20170997.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Thakur A, Roy A, Ghosh A et al (2018) Abiraterone acetate in the treatment of prostate cancer. Biomed Pharmacother 101:211–218. https://doi.org/10.1016/j.biopha.2018.02.067

    Article  PubMed  CAS  Google Scholar 

  2. GLOBOCAN (2018) Cancer fact sheets: prostate cancer. http://globocan.iarc.fr/old/FactSheets/cancers/prostate-new.asp. Accessed 23 June 2018

  3. Chen W, Zheng R, Baade PD et al (2016) Cancer statistics in china, 2015. CA Cancer J Clin 66(2):115–132. https://doi.org/10.3322/caac.21338

    Article  PubMed  Google Scholar 

  4. Chen W, Sun K, Zheng R et al (2018) Cancer incidence and mortality in China, 2014. Chin J Cancer Res 30(1):1–12. https://doi.org/10.21147/j.issn.1000-9604.2018.01.01

    Article  PubMed  PubMed Central  Google Scholar 

  5. Petrylak DP, Tangen CM, Hussain MH et al (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351(15):1513–1520. https://doi.org/10.1056/NEJMoa041318

    Article  PubMed  CAS  Google Scholar 

  6. Scher HI, Fizazi K, Saad F et al (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367(13):1187–1197. https://doi.org/10.1056/NEJMoa1207506

    Article  PubMed  CAS  Google Scholar 

  7. Al-Salama ZT (2018) Apalutamide: first global approval. Drugs 78(6):699–705. https://doi.org/10.1007/s40265-018-0900-z

    Article  PubMed  CAS  Google Scholar 

  8. Ryan CJ, Smith MR, de Bono JS et al (2013) Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368(2):138–148. https://doi.org/10.1056/NEJMoa1209096

    Article  PubMed  CAS  Google Scholar 

  9. de Bono JS, Logothetis CJ, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005. https://doi.org/10.1056/NEJMoa1014618

    Article  PubMed  PubMed Central  Google Scholar 

  10. US Food and Drug Administration (2018) ZYTIGA™ Label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202379s024lbl.pdf. Accessed 23 June 2018

  11. Acharya M, Bernard A, Gonzalez M et al (2012) Open-label, phase I, pharmacokinetic studies of abiraterone acetate in healthy men. Cancer Chemother Pharmacol 69(6):1583–1590. https://doi.org/10.1007/s00280-012-1865-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Inoue K, Shishido A, Vaccaro N et al (2015) Pharmacokinetics of abiraterone in healthy Japanese men: dose-proportionality and effect of food timing. Cancer Chemother Pharmacol 75(1):49–58. https://doi.org/10.1007/s00280-014-2616-4

    Article  PubMed  CAS  Google Scholar 

  13. European Medicines Agency (2018) Guideline on the investigation of bioequivalence. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. Accessed 23 June 2018

  14. US Food and Drug Administration (2018) Draft guideline on bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm377465.pdf. Accessed 23 June 2018

  15. World Medical Association (WMA). Declaration of Helsinki. Ethical principles for medical research involving human subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 64th WMA General Assembly, Fortaleza, Brazil, and (2013) https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed 23 June 2018

  16. International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (2018) Guideline for good clinical principles. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_2016_1109.pdf. Accessed 23 June 2018

  17. China National Drug Administration (2018) Guideline for good clinical principles. http://samr.cfda.gov.cn/WS01/CL0053/24473.html. Accessed 23 June 2018

  18. Center for Drug Evaluation of CNDA (2018) Guideline on bioequivalence studies with pharmacokinetic endpoints for generic chemical drugs. http://www.cde.org.cn/zdyz.do?method=largePage&id=227. Accessed 23 June 2018

  19. US Food and Drug Administration (2018) Bioanalytical method validation guidance for industry. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070107.pdf. Accessed 23 June 2018

  20. European Medicines Agency (2018) Abiraterone tablets 250 mg product-specific bioequivalence guidance. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/03/WC500222372.pdf. Accessed 23 June 2018

  21. Chi KN, Spratlin J, Kollmannsberger C et al (2015) Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer. J Clin Pharmacol 55(12):1406–1414. https://doi.org/10.1002/jcph.564

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Jiangxi Qingfeng Pharmaceutical Co., Ltd. (Jiang Xi, China) and the National Science and Technology Major Project (no. 2017ZX09101001-002-044). The authors would like to thank the study subjects, clinical investigators, study coordinators, CRAs, and the administrative staff at the Xuanwu Hospital who made this study possible.

Funding

This study was supported by Jiangxi Qingfeng Pharmaceutical Co., Ltd. (Jiang Xi, China) and the National Science and Technology Major Project (no. 2017ZX09101001-002-044).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Lin Li or Lan Zhang.

Ethics declarations

Conflict of interest

All the authors have no conflict of interest regarding the sponsor or the content of this article.

Ethical approval

The study protocol, protocol amendments and all applicable documents including informed consent form were reviewed and approved by the Ethic Committee of Xuanwu Hospital Capital Medical University (2017 no. 14).

Informed consent

Informed consent was obtained from all subjects prior to screening.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 58 KB)

Supplementary material 2 (PDF 58 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, C., Hu, C., Gao, D. et al. Pharmacokinetics and bioequivalence of generic and branded abiraterone acetate tablet: a single-dose, open-label, and replicate designed study in healthy Chinese male volunteers. Cancer Chemother Pharmacol 83, 509–517 (2019). https://doi.org/10.1007/s00280-018-3754-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-018-3754-x

Keywords

  • Abiraterone acetate
  • Highly variable drug
  • Intra-subject variability
  • Bioequivalence
  • LC-MS/MS