Phase I trial of pod-intravaginal rings delivering antiretroviral agents for HIV-1 prevention: Rectal drug exposure from vaginal dosing with tenofovir disoproxil fumarate, emtricitabine, and maraviroc

Autor: Richard B. Pyles, Marc M. Baum, Manjula Gunawardana, Peter A. Anton, Craig W. Hendrix, Kathleen L. Vincent, John A. Moss, Mark A. Marzinke, Lauren N. Dawson, Trevelyn J. Olive
Jazyk: angličtina
Rok vydání: 2018
Předmět:
RNA viruses
0301 basic medicine
Interstitial Fluid
Physiology
HIV Infections
Pathology and Laboratory Medicine
Gastroenterology
Pre-exposure prophylaxis
chemistry.chemical_compound
Immunodeficiency Viruses
Medicine and Health Sciences
media_common
Drug Distribution
Multidisciplinary
Pharmaceutics
Phase I clinical investigation
Vaginal delivery
Body Fluids
3. Good health
medicine.anatomical_structure
Medical Microbiology
Viral Pathogens
Vagina
Viruses
Infectious diseases
Medicine
Female
Anatomy
Pathogens
Research Article
medicine.drug
Drug
medicine.medical_specialty
Drug Research and Development
Anti-HIV Agents
media_common.quotation_subject
Science
030106 microbiology
Rectum
Viral diseases
Research and Analysis Methods
Emtricitabine
Microbiology
03 medical and health sciences
Internal medicine
Retroviruses
medicine
Humans
Clinical Trials
Pharmacokinetics
Dosing
Microbial Pathogens
Maraviroc
Pharmacology
Dose-Response Relationship
Drug
business.industry
Lentivirus
Organisms
Biology and Life Sciences
HIV
Gastrointestinal Tract
Clinical trial
Administration
Intravaginal
chemistry
HIV-1
Pre-Exposure Prophylaxis
Clinical Medicine
Drug Delivery
business
Digestive System
Zdroj: PLoS ONE, Vol 13, Iss 8, p e0201952 (2018)
PLoS ONE
ISSN: 1932-6203
Popis: Background Intravaginal rings (IVRs) can deliver antiretroviral (ARV) agents for HIV pre-exposure prophylaxis (PrEP), theoretically overcoming adherence concerns associated with frequent dosing. However, topical vaginal ARV drug delivery has not simultaneously led to sufficient rectal drug exposure to likely protect from HIV infection as a result of receptive anal intercourse (RAI). Unprotected RAI has a higher risk of infection per sex act and, for women, also can be associated with vaginal exposure during a single sexual encounter, especially in higher-risk subsets of women. The physiologically inflamed, activated, immune-cell dense colorectal mucosa is increasingly appreciated as the sexual compartment with highly significant risk; this risk is increased in the setting of co-infections. Ex vivo studies have shown that colorectal tissue and rectal fluid concentrations correlated with HIV protection. Given these important results, efforts to document colorectal compartment ARV drug concentration from pod-IVR delivery was assessed to determine if vaginal application could provide protective ARV levels in both compartments. Methodology/Principal findings A crossover clinical trial (N = 6) evaluated 7 d of continuous TDF pod-IVR use, a wash-out phase, followed by 7 d with a TDF-FTC pod-IVR. A subsequent clinical trial (N = 6) consisted of 7 d of continuous TDF-FTC-MVC pod-IVR use. Rectal fluids were collected on Day 7 at IVR removal in all three ARV-exposures (two Phase 1 trials) and drug concentrations quantified by LC-MS/MS. Median rectal fluid concentrations of TFV, the hydrolysis product of the prodrug TDF, were between 0.66 ng mg-1 (TDF pod-IVR group) and 1.11 ng mg-1 (TDF-FTC pod-IVR group), but below the analytical lower limit of quantitation in 5/6 samples in the TDF-FTC-MVC pod-IVR group. Unexpectedly, median FTC (TDF-FTC pod-IVR, 20.3 ng mg-1; TDF-FTC-MVC pod-IVR, 0.18 ng mg-1), and MVC rectal fluid concentrations (0.84 ng mg-1) were quantifiable and higher than their respective in vitro EC50 values in most samples. Due to participant burden in these exploratory trials, rectal fluid was used as a surrogate for rectal tissue, where drug concentrations are expected to be higher. Conclusions/Significance The concentrations of FTC and MVC in rectal fluids obtained in two exploratory clinical trials of IVRs delivering ARV combinations exceeded levels associated with in vitro efficacy in HIV inhibition. Unexpectedly, MVC appeared to depress the distribution of TFV and FTC into the rectal lumen. Here we show that vaginal delivery of ARV combinations may provide adherence and coitally independent dual-compartment protection from HIV infection during both vaginal and receptive anal intercourse.
Databáze: OpenAIRE
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