Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid

• Main Authors: Eric H. Decloedt (Author), Phumla Z. Sinxadi (Author), Lubbe Wiesner (Author), John A. Joska (Author), David W. Haas (Author), Gary Maartens (Author)
• Format: Book
• Published: AOSIS, 2021-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1608-9693; 2078-6751; 10.4102/sajhivmed.v22i1.1206
• Keywords: pharmacokinetics; pharmacogenetics; tenofovir; emtricitabine; cerebrospinal fluid; Public aspects of medicine; RA1-1270; Infectious and parasitic diseases; RC109-216
• Source: Southern African Journal of HIV Medicine, Vol 22, Iss 1, Pp e1-e24 (2021)

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.