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Oral cyclosporin A inhibits CD4 T cell P-glycoprotein activity in HIV-infected adults initiating treatment with nucleoside reverse transcriptase inhibitors

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Abstract

Purpose

P-glycoprotein limits the tissue penetration of many antiretroviral drugs. The aim of our study was to characterize the effects of the P-glycoprotein substrate cyclosporin A on T cell P-glycoprotein activity in human immunodeficiency virus-infected participants in the AIDS Clinical Trials Group study A5138.

Methods

We studied P-glycoprotein activity on CD4 and CD8 T cells in 16 participants randomized to receive oral cyclosporin A (n = 9) or not (n = 7) during initiation antiretroviral therapy (ART) that did not include protease or non-nucleoside reverse transcriptase inhibitors.

Results

CD4 T cell P-glycoprotein activity decreased by a median of 8 percentage points with cyclosporin A/ART (difference between cyclosporin A/ART vs. ART only, P = 0.001). Plasma trough cyclosporin A concentrations correlated with the change in P-glycoprotein activity in several T cell subsets.

Conclusions

Oral cyclosporin A can inhibit peripheral blood CD4 T cell P-glycoprotein activity. Targeted P-glycoprotein inhibition may enhance the delivery of ART to T cells.

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Acknowledgments

The authors thank the patients who participated in the study and the following investigators who contributed to A5138: Tania George (Bristol-Myers Squibb, Plainsboro, NJ); Kathy Burgner, Jane Baum, and Steve Arrington (Case Western Reserve University, Cleveland, OH); Laurie Myers and Janeen Duffy (Frontier Science and Technology Research Foundation, Buffalo, NY); Dr. Jerry M. Tolson (GlaxoSmithKline, Research Triangle, NC); Dr. W. Keith Henry (Hennipen County Medical Center, Minneapolis, MN); Dr. Elizabeth Adams and Elaine Ferguson (National Institutes of Health, Division of AIDS, Bethesda, MD); Dr. Harold A. Kessler (Rush-Presbyterian–St. Luke′s Medical Center, Chicago, IL); Nasreen Jahed and Dr. Tine De Marez (Social and Scientific Systems, Silver Spring, MD); Monique Givens (University of Colorado, Denver).

Financial interest disclosures

A5138 was supported by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (AI68636). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. Additional grant support included a Vanderbilt Clinical Research Scholars award (K12 RR17697) and K23 AT02508 (T.H.); AI38855 (L.S., M.P., H.W.); AI25879 and AI36219 (M.M.L.); AI69423 and AI50410 (C.P.); AI069439, AI54999, and MH071205 (D.W.H.). Pharmaceutical support for A5138 was provided by GlaxoSmithKline and Bristol-Myers Squibb. T.H. has received research funding from Merck & Co., Inc. D.W.H. has received research grants from Bavarian Nordic, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Merck, Tanox, and Tibotec, and is on Scientific Advisory Boards for GlaxoSmithKline and Tibotec. The other authors have no potential conflicts to declare.

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Authors and Affiliations

  1. Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, 345 24th Ave N, Suite 105, Nashville, TN, 37203, USA

    Todd Hulgan, John P. Donahue & David W. Haas

  2. Statistical and Data Analysis Center, Harvard University School of Public Health, Boston, MA, USA

    Laura Smeaton & Hongying Wang

  3. University of California-San Diego, San Diego, CA, USA

    Minya Pu

  4. Case Western Reserve University, Cleveland, OH, USA

    Michael M. Lederman

  5. Rush University Medical Center, Chicago, IL, USA

    Kimberly Smith

  6. Pfizer Inc., New York, NY, USA

    Hernan Valdez

  7. University of California-San Francisco, San Francisco, CA, USA

    Christopher Pilcher

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  1. Todd Hulgan
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  2. John P. Donahue
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  4. Minya Pu
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  8. Hernan Valdez
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  9. Christopher Pilcher
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  10. David W. Haas
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The AIDS Clinical Trials Group Study A5138 Team

Corresponding author

Correspondence to Todd Hulgan.

Additional information

These data were previously presented in part at the 13th Conference on Retroviruses and Opportunistic Infections, February 2006, Denver, CO (abstract 564).

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Hulgan, T., Donahue, J.P., Smeaton, L. et al. Oral cyclosporin A inhibits CD4 T cell P-glycoprotein activity in HIV-infected adults initiating treatment with nucleoside reverse transcriptase inhibitors. Eur J Clin Pharmacol 65, 1081–1088 (2009). https://doi.org/10.1007/s00228-009-0725-5

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  • DOI: https://doi.org/10.1007/s00228-009-0725-5

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