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Effect of Protease Inhibitors on Steady-State Pharmacokinetics of Oral Norethindrone Contraception in HIV-Infected Women

Atrio, Jessica MD, MSc*; Stanczyk, Frank Z. PhD*; Neely, Michael MD; Cherala, Ganesh PhD; Kovacs, Andrea MD§; Mishell, Daniel R. Jr MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: January 1st, 2014 - Volume 65 - Issue 1 - p 72–77
doi: 10.1097/QAI.0b013e3182a9b3f1
Clinical Science

Objective: Pharmacokinetic interactions exist between combined oral contraceptives and protease inhibitors (PI). However, such information is lacking for progestin-only oral contraception. We sought to define the steady-state pharmacokinetic interaction between norethindrone (NET) and PI in HIV-infected women.

Methods and Design: We conducted an open-label, prospective, nonrandomized trial to characterize the steady-state pharmacokinetics of serum NET in HIV-infected women receiving PI compared with a control group of HIV-infected women receiving other noninteracting drugs. After 21 days of 0.35 mg of NET ingestion once daily, serial serum samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours. The area under the curve between 0 and 72 hours after ingestion was calculated by trapezoidal approximation.

Results: Thirty-five women were enrolled, 2 withdrew. Sixteen women in the PI group and 17 controls completed the study. NET half-life and maximum concentration were not significantly different between the 2 groups. Minimum concentration of NET was significantly higher in the PI group (P = 0.01). The ratio of the geometric mean NET area under the curve in the PI group compared with controls was 1.5 (90% confidence interval: 1.21 to 1.86). NET serum concentrations were significantly higher in HIV-infected women taking a PI compared with controls (P = 0.004).

Conclusions: Coadministration of PI inhibits NET metabolism as shown by higher serum NET area under the curve levels, a surrogate marker for therapeutic contraceptive efficacy. This study supports the increased utilization of progestin-only pills in HIV-infected women receiving certain PI regimens.

*Department of Obstetrics and Gynecology; and

Laboratory of Applied Pharmacokinetics, Keck School of Medicine, University of Southern California, Los Angeles, CA;

Department of Pharmacy Practice, College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland, OR; and

§Maternal Child and Adolescent Center for Infectious Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA.

Correspondence to: Jessica Atrio, MD, MSc, 1695 Eastchester Road, Bronx, NY 10461 (e-mail: jessicaatrio@gmail.com).

Supported by the Society of Family Planning, Southern California Clinical, and Translational Science Institute (The National Institutes of Health, National Center for Research Resources, National Center for Advancing Translational Sciences) (through grant UL1TR000130 for J.A.), and the National Institutes of Health Grants (GM068968 and HD070886 for M.N.).

The authors have no conflicts of interest to disclose.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Received June 14, 2013

Accepted August 19, 2013

© 2014 by Lippincott Williams & Wilkins