Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis

Melanie R. Nicol, Katelyn A. Pastick, Joneé Taylor, Olivie C. Namuju, Joshua Rhein, Darlisha A. Williams, David B. Meya, David R. Boulware, Robert Lukande

Research output: Contribution to journalArticlepeer-review

Abstract

The central nervous system (CNS) is a known HIV reservoir, yet little is known about drug exposure in the brain. Our primary objective was to quantify exposure of three common antiretrovirals in brain tissue and compare exposures to plasma and cerebrospinal fluid (CSF). We also sought to identify pockets of brain most vulnerable to inadequate drug exposures and examine the role of meningitis in drug penetration into the CNS. Tenofovir, lamivudine, and efavirenz concentrations were measured using liquid chromatography and tandem mass spectrometry in plasma and CSF from 14 individuals with HIV, 7 with cryptococcal meningitis. In four individuals (three with meningitis) drug concentrations were also measured in 13 distinct brain tissue regions. In subjects with meningitis, geometric mean ratio (95% confidence interval) of tenofovir CSF to plasma was 66% (7–598%) and 14% (6–31%) in subjects without meningitis. Lamivudine CSF penetration was 100% (25–409%) in subjects with meningitis and 30% (24–37%) in subjects without meningitis. Tenofovir brain tissue concentrations were 36% (14–124%) of plasma and 49% (1–572%) of CSF. Lamivudine brain concentrations were 37% (23–64%) of plasma and 27% (1–104%) of CSF. Efavirenz brain tissue concentrations were 128% (108–179%) of plasma. Tissues collected postmortem provide a unique opportunity to assess drug distribution in tissues difficult to sample in living subjects. CSF is a poor surrogate for drug exposure throughout the CNS. Antiretrovirals differentially penetrate into the CNS and penetration may be enhanced by meningitis.

Original languageEnglish (US)
Pages (from-to)445-449
Number of pages5
JournalClinical and translational science
Volume12
Issue number5
DOIs
StatePublished - Sep 1 2019

Bibliographical note

Funding Information:
This work was supported by the University of Minnesota College of Pharmacy, the University of Minnesota Academic Health Center Global Health Seed Grant, the Fogarty International Center (R01NS086312, K01TW010268, and R25TW009345), the National Institute of Neurologic Diseases and Stroke (R01NS086312 and R21NS108344), the National Institute of Allergy and Infectious Diseases (K08AI134262), and the United Kingdom Medical Research Council/Welcome Trust/Department for International Development (MRC MR/M0074131/1).

Funding Information:
This work was supported by the University of Minnesota College of Pharmacy, the University of Minnesota Academic Health Center Global Health Seed Grant, the Fogarty International Center (R01NS086312, K01TW010268, and R25TW009345), the National Institute of Neurologic Diseases and Stroke (R01NS086312 and R21NS108344), the National Institute of Allergy and Infectious Diseases (K08AI134262), and the United Kingdom Medical Research Council/Welcome Trust/Department for International Development (MRC MR/M0074131/1). The authors would like to thank James Fisher and the Clinical Pharmacology Analytical Services Laboratory for drug quantification services.

Publisher Copyright:
© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

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