Pharmacokinetics of antiretrovirals in mucosal tissue

Abstract

Introduction: In the absence of an HIV vaccine or cure, antiretroviral (ARV)-based prevention strategies are being investigated to reduce HIV incidence. These prevention strategies depend on achieving effective drug concentrations at the site of HIV exposure, which is most commonly the mucosal tissue of the lower gastrointestinal tract and the female genital tract.

Areas covered: This article collates all known data regarding drug exposure in these vulnerable mucosal tissues and reviews important mechanisms of ARV drug distribution. Research papers and abstracts describing ARV pharmacokinetics (PK) in the female genital tract and lower gastrointestinal mucosal tissues available in MEDLINE® or presented at scientific conferences prior to December 2014 are reviewed in detail. Important influences on ARV mucosal tissue distribution, including protein binding, active drug transport and endogenous hormones are also reviewed.

Expert opinion: ARVs exhibit highly variable PK in mucosal tissues. In general, ARV exposure is higher in the lower gastrointestinal tract compared with the female genital tract, but concentrations required for protective efficacy are largely unknown. The expected site of HIV exposure represents an important consideration when designing and optimizing ARV-based prevention strategies.

Keywords: HIV prevention; antiretroviral; mucosal tissue; pharmacokinetics.

Figure 1. Antiretroviral Female Genital and Lower Gastrointestinal Tract Penetration Ratios

This figure reports the mucosal tissue or fluid:blood plasma area under the concentration time curve (AUC) ratios for 22 antiretrovirals stratified by class. Both single dose (open symbols) and steady state (closed symbols) are reported when available. The line of unity (mucosal tissue/fluid AUC=blood plasma AUC) is denoted by the solid reference line. In general penetration ratios tend to be higher in the lower gastrointestinal tract for most antiretrovirals. As a class nucleoside reverse transcriptase inhibitors (NRTIs) and the entry inhibitor (EI), maraviroc(MVC), tend to demonstrate a high degree of penetration (>1) into the female genital and lower gastrointestinal tracts whereas non nucleoside reverse transcriptase inhibitors (NNRTIS) and protease inhibitors (PIs) tend to exhibit low penetration (<1). ABC=abacavir, ddI=didanosine, FTC=emtricitabine, 3TC=lamivudine, d4T=stavudine, TFV=tenofovir, AZT=Zidovudine, DTG=dolutegravir, RTG=raltegravir, DLV=delavirdine, EFV=efavirenz, ETR=etravirine, NVP=nevirapine, APV=amprenavir, ATV=atazanavir, DRV=darunavir, FPV=fosamprenavir, IDV=indinavir, LPV=lopinavir, NFV=nelfinavir, RTV=ritonavir, INSTIs=integrase strand transfer inhibitors.