| Reference | 1. J Antimicrob Chemother. 2019 Aug 1;74(8):2352-2359. doi: 10.1093/jac/dkz187.<br />
Pharmacokinetics of tenofovir monoester and association with intracellular tenofovir diphosphate following single-dose tenofovir disoproxil fumarate.<br />
Brooks KM(1), Ibrahim ME(1), Castillo-Mancilla JR(2), MaWhinney S(3), Alexander K(1), Tilden S(1), Kerr BJ(1), Ellison L(1), McHugh C(1), Bushman LR(1), Kiser JJ(1), Hosek S(4), Huhn GD(4), Anderson PL(1).<br />
Author information:<br />
(1)Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus (AMC), Aurora, CO, USA. (2)Department of Medicine, School of Medicine, University of Colorado AMC, Aurora, CO, USA. (3)Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado AMC, Aurora, CO, USA. (4)Department of Medicine, Stroger Hospital of Cook County, Chicago, IL, USA.<br />
BACKGROUND: Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported.<br />
METHODS: Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models.<br />
RESULTS: Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) Tmax of 0.5 h (0.25-2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0-4 was 93.3 ng·h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng·h/mL (30.0%). Tenofovir monoester AUC0-∞ (but not tenofovir AUC0-∞) was a significant predictor of tenofovir diphosphate in both PBMC (P = 0.015) and DBS (P = 0.005), increasing by 3.8% (95% CI 0.8%-6.8%) and 4.3% (95% CI 1.5%-7.2%), respectively, for every 10 ng·h/mL increase in tenofovir monoester. CONCLUSIONS: Tenofovir monoester Cmax and AUC0-4 were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.<br />
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2. Clin Infect Dis. 2019 Nov 27;69(12):2201-2204. doi: 10.1093/cid/ciz290.<br />
Decreased Tenofovir Diphosphate Concentrations in a Transgender Female Cohort: Implications for Human Immunodeficiency Virus Preexposure Prophylaxis.<br />
Cottrell ML(1), Prince HMA(2), Schauer AP(1), Sykes C(1), Maffuid K(1), Poliseno A(1), Chun TW(3), Huiting E(3), Stanczyk FZ(4), Peery AF(5), Dellon ES(5), Adams JL(6)(7), Gay C(2), Kashuba ADM(1)(2).<br />
Author information:<br />
(1)Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics. (2)School of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill. (3)HIV Immunovirology Unit, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. (4)Keck School of Medicine, University of Southern California, Los Angeles. (5)School of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill. (6)Philadelphia College of Pharmacy, University of the Sciences, Pennsylvania. (7)Cooper University Hospital Early Intervention Program, Camden, New Jersey.<br />
Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP's active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = -0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110.<br />
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3. AIDS. 2018 Aug 24;32(13):1891-1898. doi: 10.1097/QAD.0000000000001922.<br />
Tenofovir and tenofovir-diphosphate concentrations during pregnancy among HIV-uninfected women using oral preexposure prophylaxis.<br />
Pyra M(1)(2), Anderson PL(3), Hendrix CW(4), Heffron R(1)(2), Mugwanya K(2), Haberer JE(5)(6), Thomas KK(2), Celum C(1)(2)(7), Donnell D(2)(8), Marzinke MA(4), Bukusi EA(2)(9)(10), Mugo NR(2)(10), Asiimwe S(11), Katabira E(12), Baeten JM(1)(2)(7); Partners Demonstration Study Team.<br />
Author information:<br />
(1)Department of Epidemiology. (2)Department of Global Health. (3)Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora. (4)Department of Medicine (Clinical Pharmacology), Johns Hopkins University, Baltimore. (5)Massachusetts General Hospital Global Health and Harvard Medical School. (6)Department of Medicine, Harvard Medical School, Boston. (7)Department of Medicine. (8)Vaccine and Infection Diseases and Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, USA. (9)Department of Obstetrics and Gynecology, University of Washington, Seattle. (10)Kenya Medical Research Institute (KEMRI). (11)Kabwohe Clinical Research Center. (12)Infectious Disease Institute, Makerere University, Uganda.<br />
OBJECTIVES: Pregnancy is a time of increased HIV acquisition risk and pregnancy reduces concentrations of antiretrovirals used for treatment. We assessed whether pregnancy lowers concentrations of tenofovir (TFV) and tenofovir-diphosphate (TFV-DP) among HIV-uninfected women using oral preexposure prophylaxis (PrEP).<br />
METHODS: We analyzed data from an open-label PrEP study, comparing concentrations of TFV in plasma and TFV-DP in dried blood spots (DBS) among 37 pregnant women and 97 nonpregnant women. Analyses controlled for adherence from daily electronic monitoring.<br />
RESULTS: The average plasma concentration of TFV among pregnant women was 34.7 ng/ml with 22.2 average recorded doses over the prior month versus 86.5 ng/ml with 23.1 doses among nonpregnant women. After controlling for adherence, TFV concentrations were 58% lower among pregnant women, a statistically significant difference of -50.4 ng/ml (95% CI -68.3 to -32.5). The average TFV-DP concentration was 450.3 fmol/punch among pregnant women and 636.7 fmol/punch among nonpregnant women. This difference was not statistically significant after adjusting for adherence; however, among those with quantifiable TFV-DP, concentrations were 27% lower during pregnancy [-202 fmol/punch (95% CI -384 to -19)]. Among participants with samples before and during pregnancy, there were significant decreases during pregnancy, controlling for adherence: -28.1 ng/ml TFV (95% CI -52.3 to -4.0) and -289.2 fmol/punch TFV-DP (95% CI -439.0 to -139.3).<br />
CONCLUSION: Consistent with studies among HIV-infected women on ART, we found TFV and TFV-DP concentrations were lower during pregnancy. There is no established TFV concentration threshold to achieve HIV prevention. Additional pharmacokinetic studies and studies of PrEP efficacy in pregnancy are needed.<br />
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