Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

Trezza, Christine; Kashuba, Angela D. M.

doi:10.1007/s40262-014-0148-z

Cited by 49 publications

(51 citation statements)

References 118 publications

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“…Randomized clinical trials (RCTs) for PrEP based on TFV preparations have used sparse sampling of plasma, PBMCs, or cervicovaginal fluid to correlate measured drug levels (PK) with the primary pharmacodynamic (PD) endpoint: HIV-1 seroconversion. For systemic PrEP, TFV-DP concentration in PBMCs represents an accepted metric for estimating threshold protective drug levels (23,33,(40)(41)(42). In iPrEX, an RCT where HIV-negative men who have sex with men took a daily oral combination of TDF and emtricitabine (FTC), HIV-1 protection was 92% in participants moderately adhering to the regimen, as determined by plasma TFV levels (17).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

Gunawardana

Remedios-Chan

Miller

et al. 2015

Antimicrob Agents Chemother

149

196

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e Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day ؊1 in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml ؊1 ; interquartile range [IQR], 0.60 to 1.50 ng ml ؊1 ) and tenofovir (TFV; median, 15.0 ng ml ؊1 ; IQR, 8.8 to 23.3 ng ml ؊1 ), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/10 6 cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations. O ral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention, but clinical outcomes have varied widely (1-3). Adherence to frequent dosing is burdensome to the user and has emerged as a key factor in explaining the heterogeneous efficacy outcomes of HIV-1 preexposure prophylaxis (PrEP) clinical trials (4-7). It is well established across different delivery methods that adherence to therapy is inversely related with the dosing period (8-11). Sustained-release or long-acting ARV formulations hold significant promise as a means of reducing dosing frequency, thereby increasing the effectiveness of HIV-1 PrEP.Long-acting preexposure prophylaxis (LA-PrEP) is an alternative regimen to daily dosing designed to mitigate the abovedescribed adherence challenges (12, 13). LA-PrEP has been based primarily on ARV nanoparticles for parenteral administration as injections (12,14). Dosing intervals of 1 month or longer for injectable, long-acting, nanomilled formulations of the integrase strand-transfer inhibitor cabotegravir (GSK1265744) and the nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine are undergoing clinical evaluation as possible regimens for H...

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

Gunawardana

Remedios-Chan

Miller

et al. 2015

Antimicrob Agents Chemother

149

196

View full text Add to dashboard Cite

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“…A commonly used strategy for developing PrEP agents is to test the currently available anti-HIV-1 therapeutic drugs (4,5). While this approach is rational, a major obstacle has been in defining the optimal preventive doses of these antiretrovirals which were originally formulated to reduce the viral loads to undetectable levels as measured in the peripheral blood.…”

Section: Introductionmentioning

confidence: 99%

“…For prevention however, a different dose of the drug might be necessary to reach effective exposure (concentration) in the vaginal and rectal mucosa wherein the initial infection takes hold (6). Therefore, a major task in the PrEP field is to evaluate the capacity for mucosal accumulation of various ARTs to ascertain their potential application for long-term preventive use (4,5). …”

Section: Introductionmentioning

confidence: 99%

Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

Veselinović

Yang²,

Sykes³

et al. 2016

Virology

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Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data.

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“…A poor drug distribution in this compartment could lead to suboptimal concentrations, allowing HIV replication. The distribution of antiretroviral drugs in the genital tract has been reported to be drug specific and highly variable among individuals even for the same drug (7)(8)(9). For some protease inhibitors, SP concentrations have been reported to be lower than BP concentrations, whereas indinavir SP concentrations have been reported to be much higher (9).…”

mentioning

confidence: 99%

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

Valade

Bouazza

Lui

et al. 2017

Antimicrob Agents Chemother

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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.

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Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

Cited by 49 publications

References 118 publications

Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

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

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