Lack of Prophylactic Efficacy of Oral Maraviroc in Macaques despite High Drug Concentrations in Rectal Tissues

Massud, Ivana; Aung, Wutyi; Martin, Amy; Bachman, Shanon; Mitchell, James; Aubert, Rachael D.; Tsegaye, Theodros Solomon; Kersh, Ellen N.; Pau, Chou Pong; Heneine, Walid; Garcı́a-Lerma, J. Gerardo

doi:10.1128/jvi.01204-13

Cited by 54 publications

(58 citation statements)

References 45 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent work by Massud et al suggested that rectal delivery of maraviroc gels lacks efficacy in a macaque SHIV challenge model and may be complicated by effects of rectally applied maraviroc on populations of CD3 ϩ /CCR5 ϩ cells (40). It remains to be seen if maraviroc can serve as an effective microbicide in humans, either intravaginally or rectally.…”

Section: Discussionmentioning

confidence: 99%

Electrospun Solid Dispersions of Maraviroc for Rapid Intravaginal Preexposure Prophylaxis of HIV

Ball

Woodrow

2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The development of topical anti-human immunodeficiency virus (HIV) microbicides may provide women with strategies to protect themselves against sexual HIV transmission. Pericoital drug delivery systems intended for use immediately before sex, such as microbicide gels, must deliver high drug doses for maximal effectiveness. The goal of achieving a high antiretroviral dose is complicated by the need to simultaneously retain the dose and quickly release drug compounds into the tissue. For drugs with limited solubility in vaginal gels, increasing the gel volume to increase the dose can result in leakage. While solid dosage forms like films and tablets increase retention, they often require more than 15 min to fully dissolve, potentially increasing the risk of inducing epithelial abrasions during sex. Here, we demonstrate that water-soluble electrospun fibers, with their high surface area-to-volume ratio and ability to disperse antiretrovirals, can serve as an alternative solid dosage form for microbicides requiring both high drug loading and rapid hydration. We formulated maraviroc at up to 28 wt% into electrospun solid dispersions made from either polyvinylpyrrolidone or poly(ethylene oxide) nanofibers or microfibers and investigated the role of drug loading, distribution, and crystallinity in determining drug release rates into aqueous media. We show here that water-soluble electrospun materials can rapidly release maraviroc upon contact with moisture and that drug delivery is faster (less than 6 min under sink conditions) when maraviroc is electrospun in polyvinylpyrrolidone fibers containing an excipient wetting agent. These materials offer an alternative dosage form to current pericoital microbicides.

show abstract

Section: Discussionmentioning

confidence: 99%

Electrospun Solid Dispersions of Maraviroc for Rapid Intravaginal Preexposure Prophylaxis of HIV

Ball

Woodrow

2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The observed median steady-state MVC level of 20 g g Ϫ1 (40 M) in vaginal tissues was 3,000 times higher than the highest 90% inhibitory concentration, suggesting possible favorable pharmacodynamic outcomes. However, in a macaque model involving rectal exposure, MVC concentrations in rectal secretions that were predicted to provide prophylactic efficacy (C max , 10.2 g ml Ϫ1 ) failed to protect macaques from SHIV infection (26), suggesting that prophylactic efficacy cannot be easily predicted based on MVC tissue levels. Additional efficacy studies in macaques with MVC alone and in combination with other ARVs are needed.…”

Section: Discussionmentioning

confidence: 99%

“…Levels of TDF, TFV, FTC, and MVC in vaginal fluid, cervicovaginal lavage (CVL) fluid, vaginal tissue homogenate, and plasma samples were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using published methods (15,18,25,26). The lower limits of quantitation (LLOQs) for these analytes in the aforementioned sample matrices are presented in Table 2.…”

Section: Materials Tenofovir Disoproxil Fumarate (Tdf) and Emtricitamentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Preliminary studies with macaques have demonstrated that oral administration of MVC (44 mg/kg) alone is insufficient to prevent HIV infection despite high drug concentration in rectal tissues 24 h prior to inoculation [55]. Nonetheless, MVC has been pushed to human trials in the NEXT-PrEP (Novel Exploration of Therapeutics for PreExposure Prophylaxis) study although no data on the outcome of the study are available at the time of this writing [56].…”

Section: First-generation Ccr5 Antagonistsmentioning

confidence: 99%

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

Kim

Giesler

Tahirovic

et al. 2016

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

Introduction The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists. Areas covered This review aims to survey the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies. Expert opinion The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.

show abstract

Lack of Prophylactic Efficacy of Oral Maraviroc in Macaques despite High Drug Concentrations in Rectal Tissues

Cited by 54 publications

References 45 publications

Electrospun Solid Dispersions of Maraviroc for Rapid Intravaginal Preexposure Prophylaxis of HIV

Electrospun Solid Dispersions of Maraviroc for Rapid Intravaginal Preexposure Prophylaxis of HIV

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

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

Contact Info

Product

Resources

About