1. The effect of depot medroxyprogesterone acetate on tenofovir alafenamide in rhesus macaques.
- Author
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Daly MB, Sterling M, Holder A, Dinh C, Nishiura K, Khalil G, García-Lerma JG, and Dobard C
- Subjects
- Animals, Anti-HIV Agents analysis, Anti-HIV Agents blood, Anti-HIV Agents pharmacology, Drug Interactions, Female, HIV Infections drug therapy, Leukocytes, Mononuclear drug effects, Macaca mulatta, Medroxyprogesterone Acetate analysis, Medroxyprogesterone Acetate blood, Medroxyprogesterone Acetate pharmacology, Models, Animal, Tenofovir analysis, Tenofovir blood, Tenofovir pharmacology, Anti-HIV Agents administration & dosage, Contraceptive Agents, Female administration & dosage, Medroxyprogesterone Acetate administration & dosage, Tenofovir administration & dosage
- Abstract
Prevention of HIV infection and unintended pregnancies are public health priorities. In sub-Saharan Africa, where HIV prevalence is highest, depot medroxyprogesterone acetate (DMPA) is widely used as contraception. Therefore, understanding potential interactions between DMPA and antiretrovirals is critical. Here, we use a macaque model to investigate the effect of DMPA on the pharmacology of the antiretroviral tenofovir alafenamide (TAF). Female rhesus macaques received 30 mg of DMPA (n = 9) or were untreated (n = 9). Macaques received a human equivalent dose of TAF (1.5 mg/kg) orally by gavage. Tenofovir (TFV) and TFV-diphosphate (TFV-DP) were measured in blood, secretions, and tissues over 72 h. The median area under the curve (AUC
0-72h ) values for TFV-DP in peripheral blood mononuclear cells were similar in DMPA-treated (6991 fmol*h/106 cells) and untreated controls (5256 fmol*h/106 cells) (P = 0.174). Rectal tissue TFV-DP concentrations from DMPA+ animals [median: 20.23 fmol/mg of tissue (range: 4.94-107.95)] were higher than the DMPA- group [median: below the limit of quantification (BLOQ-11.92)], (P = 0.019). TFV-DP was not detectable in vaginal tissue from either group. A high-dose DMPA treatment in macaques was associated with increased rectal TFV-DP levels, indicating a potential tissue-specific drug-drug interaction. The lack of detectable TFV-DP in the vaginal tissue warrants further investigation of PrEP efficacy with single-agent TAF products. DMPA did not affect systemic TAF metabolism, with similar PBMC TFV-DP in both groups, suggesting that DMPA use should not alter the antiviral activity of TAF., (Published by Elsevier B.V.)- Published
- 2021
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