Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations.
Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100-400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations.
Clinical Virology Department, Gilead Sciences, Foster City, California, United States of America.
Christian
C
Callebaut
Clinical Virology Department, Gilead Sciences, Foster City, California, United States of America.
Yang
Y
Liu
Drug Metabolism Department, Gilead Sciences, Foster City, California, United States of America.
Darius
D
Babusis
Drug Metabolism Department, Gilead Sciences, Foster City, California, United States of America.
Adrian
A
Ray
Clinical Virology Department, Gilead Sciences, Foster City, California, United States of America.
Michael
M
Miller
Clinical Virology Department, Gilead Sciences, Foster City, California, United States of America.
Kathryn
K
Kitrinos
D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000409:Alanine; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003603:Cytotoxins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D000068698:Tenofovir / Q000031:analogs & derivatives; D013997:Time Factors
D003603:Cytotoxins; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine