CSPT 2011 - Bioequivalence Studies of Drugs Prescribed Mainly for Women

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Iain J McGilveray


Pharmacokinetics, bioavailability, bioequivalence, pregnancy, sex differences


The basic components of pharmacokinetics are absorption, distribution, metabolism, and excretion. During pregnancy there may be changes in one or many of these components. Early drug studies did not include a representative proportion of women, however, researchers as well as regulators agree that studies on the sex differences in the disposition of drugs are important, but at what stage in the clinical trial process? Except for drugs used only in women, such as those for estrogen-dependent breast cancer, caution prevails and the differences are usually studied at phase 3. Studies in pregnant women are much rarer but some do get done, e.g., with antivirals and antimalarials, where the positive risk-benefit of these agents is the likelihood that fetal transfer of these drugs might help protect the fetus. Women are being included in pharmacokinetic studies for new drug applications in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), U.S. Food and Drug Administration (FDA), and Health Canada (HC) guidances. A new look at bioequivalence studies, to compare results in men and women, would help determine if interactions of formulation and gender are a problem.

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1. U.S. Food and Drug Administration. Regulatory Information. Evaluation of Gender Differences in Clinical Investigations - Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators. (Page last updated October 19, 2010) http://www.fda.gov/RegulatoryInformation/Guid ances/ucm126552.htm (July 15, 2011).
2. U.S. Food and Drug Administration. Guidance for Industry. Pharmacokinetics in Pregnancy – Study Design, Data Analysis, and Impact on Dosing and Labeling. (October 2004) www.fda.gov/downloads/Drugs/.../Guidances/uc m072133.pdf (July 15, 2011).3.
3. Health Canada. Drugs and Health Products. Policy Issue from the Drugs Directorate: Inclusion of Women in Clinical Trials During Drug Development. (May 27, 1997) http://www.hc-sc.gc.ca/dhpmps/ prodpharma/applicdemande/ pol/women_femmes_pol-eng.php (July 15, 2011).
4. Yang Y, Carlin AS, Faustino PJ, Motta MI, Hamad ML, He R, Watanuki Y, Pinnow EE, Khan MA. Participation of women in clinical trials for new drugs approved by the food and drug administration in 2000-2002. J Womens Health (Larchmt) 2009;18(3):303-10.
5. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). http://www.ich.org (July 15, 2011).
6. Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet 2003;42(2):107-21.
7. Beierle I, Meibohm B, Derendorf H. Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther 1999;37(11):529-47.
8. Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol. 2011;2011:187103. Epub 2011 Feb 23. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC 3051160/pdf/JBB2011-187103.pdf (July 16, 2011).
9. Ammon E, Schäfer C, Hofmann U, Klotz U. Disposition and first-pass metabolism of ethanol in humans: is it gastric or hepatic and does it depend on gender? Clin Pharmacol Ther 1996;59(5): 503-13.
10. Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Chayes ZW, Schaefer C, Lieber CS. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res 2001;25(4):502- 7.
11. Ramchandani VA, Bosron WF, Li TK. Research advances in ethanol metabolism. Pathol Biol (Paris) 2001;49(9):676-82.
12. Health Canada. Drugs and Health Products. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations Used for Systemic Effects. (Modified August 14, 2009) http://www.hc-sc.gc.ca/dhpmps/ prodpharma/applic-demande/guideld/ bio/bio-a-eng.php (July 16, 2011).
13. Yu LX for the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Approaches to demonstrate bioequivalence of narrow therapeutic index drugs. (July 26, 2011) http://www.fda.gov/downloads/AdvisoryCommi ttees/CommitteesMeetingMaterials/Drugs/Advis oryCommitteeforPharmaceuticalScienceandClin icalPharmacology/UCM266777.pdf (August 9, 2011).
14. U.S. Food and Drug Administration. Guidance for Industry, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. (March 2003, Revision 1) http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/U CM070124.pdf (August 10, 2011).
15. Chen ML, Lee SC, Ng MJ, Schuirmann DJ, Lesko LJ, Williams RL. Pharmacokinetic analysis of bioequivalence trials: implications for sex-related issues in clinical pharmacology and biopharmaceutics. Clin Pharmacol Ther 2000;68(5):510-521.
16. U.S. Food and Drug Administration. Drugs. Bioequivalence Recommendations for Specific Products. (Last Updated July 5, 2011) http://www.fda.gov/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm075207.h tm (July 16, 2011).
17. Duchesnay Inc. Data on file.
18. Health Canada Scientific Advisory Panel on Bioequivalence Requirements for Gender- Specific Drug Products (SAP-GSDP). Bioequivalence Requirements for Gender- Specific Drug Products (GSDP). (Record of Proceedings for meeting of June 2, 2011) http://www.hc-sc.gc.ca/dhpmps/ alt_formats/pdf/prodpharma/activit/sciconsult/ gender-sexe/sapgsdp_gcsmss_m_bioeng. pdf (August 9, 2011).