Penetration of Tenofovir and Emtricitabine in Mucosal Tissues: Implications for Prevention of HIV-1 Transmission

cVaginal rapidly disintegrating tablets (RDTs) containing tenofovir (TFV) or TFV and emtricitabine (FTC) were evaluated for safety and pharmacokinetics in pigtailed macaques. Two separate animal groups (n ‫؍‬ 4) received TFV (10 mg) or TFV-FTC (10 mg each) RDTs, administered near the cervix. A third group (n ‫؍‬ 4) received 1 ml TFV gel. Blood plasma, vaginal tissue biopsy specimens, and vaginal fluids were collected before and after product application at 0, 0.5, 1, 4, and 24 h. A disintegration time of <30 min following vaginal application of the RDTs was noted, with negligible effects on local inflammatory cytokines, vaginal pH, and microflora. TFV pharmacokinetics were generally similar for both RDTs and gel, with peak median concentrations in vaginal tissues and vaginal secretions being on the order of 10 4 to 10 5 ng/g (147 to 571 M) and 10 6 ng/g (12 to 34 mM), respectively, at 1 to 4 h postdose. At 24 h, however, TFV vaginal tissue levels were more sustained after RDT dosing, with median TFV concentrations being approximately 1 log higher than those with gel dosing. FTC pharmacokinetics after combination RDT dosing were similar to those of TFV, with peak median vaginal tissue and fluid levels being on the order of 10 4 ng/g (374 M) and 10 6 ng/g (32 mM), respectively, at 1 h postdose with levels in fluid remaining high at 24 h. RDTs are a promising alternative vaginal dosage form, delivering TFV and/or FTC at levels that would be considered inhibitory to simian-human immunodeficiency virus in the macaque vaginal microenvironment over a 24-h period.

Section: Discussionmentioning

confidence: 53%

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confidence: 99%

Pharmacokinetic and Safety Analyses of Tenofovir and Tenofovir-Emtricitabine Vaginal Tablets in Pigtailed Macaques

Pereira¹,

Clark

Friend

et al. 2014

“…Consistent with this, we also have not shown OAT1 expression in vaginal biopsy specimens. It has been speculated that low-level OAT1 expression in colonic tissue combined with high colorectal luminal drug concentrations contributed to the 100-fold higher TFV levels in colorectal than vaginal tissue after oral dosing (38,39). The notion that OATs mediate TFV uptake comes primarily from in vitro studies using transfected cells or Xenopus oocytes overexpressing the transporters (15,23,29).…”

Section: Discussionmentioning

confidence: 99%

Differential Mechanisms of Tenofovir and Tenofovir Disoproxil Fumarate Cellular Transport and Implications for Topical Preexposure Prophylaxis

Taneva

Crooker

Park

et al. 2016

Intravaginal rings releasing tenofovir (TFV) or its prodrug, tenofovir disoproxil fumarate (TDF), are being evaluated for HIV and herpes simplex virus (HSV) prevention. The current studies were designed to determine the mechanisms of drug accumulation in human vaginal and immune cells. The exposure of vaginal epithelial or T cells to equimolar concentrations of radiolabeled TDF resulted in over 10-fold higher intracellular drug levels than exposure to TFV. Permeability studies demonstrated that TDF, but not TFV, entered cells by passive diffusion. TDF uptake was energy independent but its accumulation followed nonlinear kinetics, and excess unlabeled TDF inhibited radiolabeled TDF uptake in competition studies. The carboxylesterase inhibitor bis-nitrophenyl phosphate reduced TDF uptake, suggesting saturability of intracellular carboxylesterases. In contrast, although TFV uptake was energy dependent, no competition between unlabeled and radiolabeled TFV was observed, and the previously identified transporters, organic anion transporters ( T opical preexposure prophylaxis (PrEP) with tenofovir (TFV)-based drugs could provide a female-initiated method for the prevention of HIV and genital herpes simplex virus (HSV) infections in women (1). Pericoital dosing with 1% vaginal TFV gel reduced HIV acquisition by 39% overall and by 54% in highly adherent women (2, 3) and reduced HSV-2 acquisition by 51% in the CAPRISA 004 trial (4). However, the same gel did not provide protection against HIV in the Vaginal and Oral Interventions to Control the Epidemic (VOICE) and Follow-On Consortium for Tenofovir Studies (FACTS) 001 phase 3 trials, presumably reflecting low adherence (5, 6). Women with detectable TFV in their plasma at the first quarterly visit were less likely to acquire HIV than women with no drug detected (adjusted hazard ratio, 0.34; 95% confidence interval [CI], 0.13 to 0.87; P ϭ 0.02) in a secondary analysis of VOICE data, but the interpretation of this is complex, as women at highest risk for HIV acquisition were less likely to be adherent (5). These findings underscore the need for drugs and delivery systems that mitigate the difficulties associated with adherence.Intravaginal rings (IVRs) designed to deliver TFV and tenofovir disoproxil fumarate (TDF) are currently in early clinical development (7,8). A TDF ring completely protected macaques against 16 weekly intravaginal challenges with simian HIV (8) and also was highly protective in more susceptible, medroxyprogesteronetreated animals (9). Nonhuman primate challenge studies with the TFV IVR have not been published. Consistent with in vitro antiviral studies, 0.3% TDF gel provided significantly greater protection than 1% TFV gel in mice challenged intravaginally with HSV-2 (10). Moreover, the 0.3% TDF gel demonstrated significantly greater protection than 1% TFV gel in mice transgenic for human CD4, CCR5, and cyclin T1 against HIV and HSV-2 (11). These findings may reflect differences in drug pharmacokinetics (PK).The mechanisms of TFV and TDF cellular tran...

“…Thus, the TFV SP-to-BP concentration ratio appears to be variable depending on the time elapsed between drug intake and sampling. Another study has focused on a TFV single-dose administration and has reported an SP-to-BP exposures ratio of 1.0 (16). However, that study included a small number of subjects (n ϭ 8 men) and examined only the final phase of decay of TFV pharmacokinetics (PK) (from 24 h to 14 days).…”

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confidence: 99%

“…Available data on tenofovir (TFV) SP concentrations are sparse, although this drug is recommended as a preferred choice in first-line regimens for HIV treatment and postexposure prophylaxis and a large body of evidence from trials using TFV-based regimens now supports the concepts of "treatment as prevention" and "preexposure prophylaxis" (11,12). Four studies have suggested an accumulation of TFV in the male genital tract to different extents (13)(14)(15)(16). Mean TFV SP-to-BP concentrations ratios have been estimated at 2.8 (n ϭ 4 men) and 3.3 (n ϭ 15 men) for various sampling times (13,14).…”

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confidence: 99%

Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Valade

Bouazza

Lui

et al. 2017

The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC 0 -24 ]) were higher in SP than in BP (median AUC 0 -24 , 7.01 versus 2.97 mg · liter Ϫ1 · h, respectively). The median (range) SP-to-BP AUC 0 -24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC 0 -24 or TFV SP-to-BP AUC 0 -24 ratio on spVL was not significant (P ϭ 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.