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Author Notes:

Correspondence and request for reprints: Ighovwerha Ofotokun, 49 Jesse Hill Jr Dr. SE, Atlanta, Georgia 30303, (p) 404-616-0659, (f) 404-616-9702, iofotok@emory.edu.

C.D.L and I.O. were lead study investigators, designed and wrote the study protocol, acquired/analyzed/interpreted data, and wrote and critically reviewed the article. A.N.S was a study investigator and wrote and critically reviewed the manuscript. K.R-W and E.P.A performed assays for plasma and CSF tenofovir and emtricitabine quantification and wrote and critically reviewed the article. A.V conducted all processing of plasma and CSF, contributed to study design, and wrote and critically reviewed the manuscript.

We are grateful to the faculty, staff, and research participants at the Ponce de Leon Center for their time and dedication to this project.

Conflicts of Interest: C.D.L received grant funding as a Bristol-Myers Squibb Virology Fellow to support conduct of this study. I.O has received funding from Bristol-Myers Squibb.

Subjects:

Research Funding:

C.D.L and A.N.S. received support from the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 and KL2TR000455.

This work is also supported by the Emory CFAR (P30 AI050409).

A.N.S. received support from the National Institutes of Allergy and Infectious Diseases (1K23AI114401-01).

Keywords:

  • Pharmacology & Pharmacy
  • HIV
  • AIDS
  • central nervous system
  • clinical pharmacology
  • P-GLYCOPROTEIN
  • DRUGS
  • PENETRATION
  • TRANSPORTER
  • INFECTION
  • DARUNAVIR

Cerebrospinal fluid concentrations of tenofovir and emtricitabine in the setting of HIV-1 protease inhibitor-based regimens

Tools:

Journal Title:

Journal of Clinical Pharmacology

Volume:

Volume 56, Number 4

Publisher:

, Pages 492-496

Type of Work:

Article | Post-print: After Peer Review

Abstract:

In the combination antiretroviral therapy (cART) era, prevalence of HIV-associated neurocognitive disorders (HAND) remains high: 36.2-44.8%, contributing to morbidity and mortality. Suboptimal control of HIV in the central nervous system (CNS) likely plays a role in this phenomenon, as supported by elevated neopterin and detectable HIV-1 RNA in cerebrospinal fluid (CSF) of patients on long term cART. Studies have shown that limited CNS penetration by antiretroviral (ARV) drugs is associated with HAND. Multiple factors impact CNS drug penetration, including molecular size, lipophilicity, plasma protein binding, and affinity for efflux pump transporters. For example, the ATP-binding cassette (ABC) superfamily of efflux transporters, including p-glycoprotein and multidrug-resistance associated proteins (MRPs), are expressed at blood-brain and blood-CSF barriers and can limit drug disposition. Because many ARVs are substrates and/or inhibitors of ABC transporters, complex drug-drug interactions can occur. Specifically, protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV) are common in cART regimens when given with ritonavir (RTV) plus a backbone of tenofovir disoproxil fumarate (TDF), the tenofovir (TFV) pro-drug, and emtricitabine (FTC). Both ATV and DRV inhibit p-glycoprotein and MRP-1; these transporters are found at blood-brain and blood-CSF barriers and are important for TFV and FTC transport. We compared CSF TFV and FTC concentrations between patients receiving two different RTV-boosted PI regimens: ATV vs DRV. We also examined associations between CSF drug concentrations and CSF HIV-1 RNA detection.

Copyright information:

© 2015, The American College of Clinical Pharmacology

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