Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues

To, Elaine; Hendrix, Craig W.; Bumpus, Namandjé N.

doi:10.1016/j.bcp.2013.08.013

Cited by 27 publications

(31 citation statements)

References 22 publications

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“…Pharmacokinetic studies of intravenously, intramuscularly, and orally administered ARVs have shown a differential deposition of drugs in female genital and rectal compartments. Higher drug levels are typically found in the rectal tissue than in the female genital tract (33,34), and topically applied drugs are metabolized differently in the vaginal and rectal mucosae (35). However, in the context of a topically applied preparation of nAbs, where pharmacokinetic coverage is limited to the lumen, those observations do not explain why higher concentrations of topically applied nAbs are required to prevent viral transmission in cervical tissue than in colonic tissue.…”

Section: Discussionmentioning

confidence: 99%

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Scott

Park

Dezzutti

2016

Antimicrob Agents Chemother

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cBroadly neutralizing monoclonal antibodies (nAbs) specific for HIV are being investigated for use in HIV prevention. Due to their ability to inhibit HIV attachment to and entry into target cells, nAbs may be suitable for use as topical HIV microbicides. As such, they would present an alternative intervention for individuals who may not benefit from using antiretroviral-based products for HIV prevention. We theorize that nAbs can inhibit viral transmission through mucosal tissue, thus reducing the incidence of HIV infection. The efficacy of the PG9, PG16, VRC01, and 4E10 antibodies was evaluated in an ex vivo human model of mucosal HIV transmission. nAbs reduced HIV transmission, causing 1.5-to 2-log 10 reductions in HIV replication in ectocervical tissues and Ϸ3-log 10 reductions in HIV replication in colonic tissues over 21 days. These antibodies demonstrated greater potency in colonic tissues, with a 50-fold higher dose being required to reduce transmission in ectocervical tissues. Importantly, nAbs retained their potency and reduced viral transmission in the presence of whole semen. No changes in tissue viability or immune activation were observed in colonic or ectocervical tissue after nAb exposure. Our data suggest that topically applied nAbs are safe and effective against HIV infection of mucosal tissue and support further development of nAbs as a topical microbicide that could be used for anal as well as vaginal protection.

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Section: Discussionmentioning

confidence: 99%

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Scott

Park

Dezzutti

2016

Antimicrob Agents Chemother

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“…6). Paired vaginal fluid and tissue ARV drug levels proximal and distal to the IVR on day 7 and day 22 were poorly correlated, suggesting that mucosal uptake and distribution are dependent on host characteristics such as menstrual status, the structure of the vaginal epithelium, and expression of membrane transporters (42) and ARV drug-metabolizing enzymes (43) in addition to xenobiotic physicochemical characteristics. Overall, the drug distribution in vaginal fluids and tissues was homogeneous, with few statistically significant concentration gradients extending distally from the IVR.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

Moss

Srinivasan

Smith

et al. 2014

Antimicrob Agents Chemother

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Preexposure prophylaxis (PrEP) using FDA-approved antiretroviral (ARV) drugs is emerging as a promising strategy for the prevention of sexual HIV infection. There is growing consensus that a combination of ARV agents, analogous to highly active antiretroviral therapy (HAART), likely is essential for optimally effective PrEP (1, 2). Oral administration of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) (Truvada; Gilead Sciences, Inc.) is the first regimen approved by the FDA to reduce the risk of HIV infection in uninfected individuals (http://www.fda.gov/NewsEvents/Newsroom /PressAnnouncements/ucm312210.htm). Three recent clinical trials demonstrated that oral ARV regimens using the combination of TDF and FTC can be effective in susceptible men, women, and partners of HIV-infected individuals (3-5). However, the relative risk reduction in these trials varied widely (from 44 to 75%), and a study in which women used a daily oral TDF-FTC regimen was stopped early due to futility. A critical factor driving success in these trials appears to involve sustaining high levels of adherence to frequent dosing (6).It is well established across different delivery methods that adherence to therapy is inversely related to the dosing period (7-10). Controlled topical delivery of ARV drugs using intravaginal rings (IVRs) is thought to improve adherence (11) and to provide sustained mucosal levels independent of coitus and daily dosing (12). The delivery of two or more ARV drugs from conventional IVR designs involves significant technological and manufacturing hurdles. To meet these challenges, we have developed a novel IVR technology, the pod-IVR (13), that enables rapid development of devices capable of delivering multiple agents over a wide range of target delivery rates and aqueous solubilities (14-16). We recently published the design and 28-day pharmacokinetic (PK) evaluation in sheep of a five-drug pod-IVR as a proof-of-concept, advanced multipurpose prevention technology (MPT), combining three ARV drugs from different mechanistic classes (tenofovir [TFV], nevirapine, and saquinavir) with a proven estrogen-progestogen contraceptive for prevention of HIV infection and unintended pregnancy (17).Here we present the first report of an IVR delivering TDF and FTC, as well as the first report of a triple-combination IVR delivering TDF, FTC, and maraviroc (MVC) (an entry inhibitor/antagonist of chemokine receptor 5 [CCR5]). Preliminary local safety and pharmacokinetic (PK) findings for these devices were determined in pig-tailed macaques, which are considered by many to represent the most relevant animal model for HIV vaginal PrEP studies (15,18,19). Steady-state drug levels for all three ARV agents in vaginal fluids were sustained over the 28-day study period, with corresponding vaginal tissue concentrations suggesting putative efficacy in preventing HIV infection.

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“…Recently, DPV was shown to be differentially metabolized in mucosal tissues that will be exposed to a topical product. In vaginal and colonic tissue, DPV metabolism can be attributed to cytochrome P450 (CYP), while in colonic tissue, only UDP-glucuronosyltransferase was also shown to metabolize DPV (29). The activity of the metabolites is unknown, but they may be involved in the enhanced activity observed in colonic tissue presented here.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic Activity of Dapivirine and Maraviroc Single Entity and Combination Topical Gels for HIV-1 Prevention

et al. 2015

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Purpose Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels designed to prevent mucosal HIV transmission. Methods 0.05% DPV, 0.1% MVC, 0.05% DPV/0.1% MVC and placebo gels were evaluated for pH, viscosity, osmolality, and in vitro release. In vitro assays and mucosal tissues were used to evaluate anti-HIV activity. Viability (Lactobacilli only) and epithelial integrity in cell lines and mucosal tissues defined safety. Results The gels were acidic and viscous. DPV gel had an osmolality of 893 mOsm/kg while the other gels had an osmolality of <100 mOsm/kg. MVC release was similar from the single and combination gels (~5 μg/cm2/min1/2), while DPV release was 10-fold less from the single as compared to the combination gel (0.4331 μg/cm2/min1/2). Titrations of the gels showed 10-fold more drug was needed to protect ectocervical than colonic tissue. The combination gel showed ~10- and 100-fold improved activity as compared to DPV and MVC gel, respectively. All gels were safe. Conclusions The DPV/MVC gel showed a benefit blocking HIV infection of mucosal tissue compared to the single entity gels. Combination products with drugs affecting unique steps in the viral replication cycle would be advantageous for HIV prevention.

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Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues

Cited by 27 publications

References 22 publications

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

Pharmacodynamic Activity of Dapivirine and Maraviroc Single Entity and Combination Topical Gels for HIV-1 Prevention

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