Original Research

Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid

Eric H. Decloedt, Phumla Z. Sinxadi, Lubbe Wiesner, John A. Joska, David W. Haas, Gary Maartens
Southern African Journal of HIV Medicine | Vol 22, No 1 | a1206 | DOI: https://doi.org/10.4102/sajhivmed.v22i1.1206 | © 2021 Eric H. Decloedt, Phumla Z. Sinxadi, Lubbe Wiesner, John A. Joska, David W. Haas, Gary Maartens | This work is licensed under CC Attribution 4.0
Submitted: 22 December 2020 | Published: 28 April 2021

About the author(s)

Eric H. Decloedt, Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town; Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
Phumla Z. Sinxadi, Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
Lubbe Wiesner, Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
John A. Joska, Department of Psychiatry and Mental Health, Health Sciences, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
David W. Haas, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee; Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, United States
Gary Maartens, Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa


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Abstract

Background: Blood-cerebrospinal fluid (CSF) barrier transporters affect the influx and efflux of drugs. The antiretrovirals tenofovir and emtricitabine may be substrates of blood-brain barrier (BBB) and blood-CSF barrier transporters, but data are limited regarding the pharmacogenetics and pharmacokinetics of their central nervous system (CNS) penetration.

Objectives: We investigated genetic polymorphisms associated with CSF disposition of tenofovir and emtricitabine.

Method: We collected paired plasma and CSF samples from 47 HIV-positive black South African adults who were virologically suppressed on efavirenz, tenofovir and emtricitabine. We considered 1846 single-nucleotide polymorphisms from seven relevant transporter genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, SLCO1B1 and ABCC4) and 782 met a linkage disequilibrium (LD)-pruning threshold.

Results: The geometric mean (95% confidence interval [CI]) values for tenofovir and emtricitabine CSF-to-plasma concentration ratios were 0.023 (0.021–0.026) and 0.528 (0.460–0.605), respectively. In linear regression models, the lowest p-value for association with the tenofovir CSF-to-plasma ratio was ABCB1 rs1989830 (p = 1.2 × 10−3) and for emtricitabine, it was ABCC5 rs11921035 (p = 1.4 × 10−3). None withstood correction for multiple testing.

Conclusion: No genetic polymorphisms were associated with plasma, CSF concentrations or CSF-to-plasma ratios for either tenofovir or emtricitabine.


Keywords

pharmacokinetics; pharmacogenetics; tenofovir; emtricitabine; cerebrospinal fluid

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