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 HIV exposure which is most commonly the mucosal tissues 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 antiretroviral pharmacokinetics 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 pharmacokinetics in mucosal tissues. In general, antiretroviral exposure is higher in the lower gastrointestinal tract compared to 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 antiretroviral based prevention strategies.

Nondaily preexposure prophylaxis for HIV prevention

“…(22, 29, 30) Indeed, high activity has been observed for TDF-containing PrEP regimens in clinical trials among MSM,(3, 31, 32) as alluded to above and discussed further below. A potential mechanism for high TFV in the rectal tissue may be its ~30% bioavailability (33) such that 70% of the dose remains in the gastrointestinal tract providing high local concentrations.…”

“…Vaginal and rectal drug distribution has been elucidated for multiple antiretrovirals (see reviews(14, 22)) including the current oral PrEP agents, tenofovir and emtricitabine. These agents are nucleos(t)ide analogs that require phosphorylation in cells for pharmacologic activation.…”

“…(5, 6) It is possible that differential drug penetration in mucosal tissue, as described above, could at least partly explain these findings, but the confidence intervals are wide and inconclusive . (22, 40) Nevertheless, the differences in mucosal PK may imply that non-daily dosing such as event-driven dosing may have less pharmacokinetic forgiveness for cervicovaginal or possibly penile exposures compared with rectal exposures. This should be an area of more research in terms of non-daily PrEP for vaginal and penile HIV prevention.…”

“…(22, 40) This potential lack of adherence forgiveness should be a consideration in testing future PrEP modalities in women.…”

Distinct Pharmacodynamic Activity of Rilpivirine in Ectocervical and Colonic Explant Tissue

“…The NNRTI drug class has only a limited affinity for transporters that would influence the cell influx or efflux of RPV. However, NNRTI tissue penetration is generally low (31), and the tissue RPV concentration/ blood plasma RPV concentration ratio was previously found to be less than 1 but to be higher for rectal tissue than vaginal tissue (5,6), indicating the better penetration of RPV into colonic tissue than female genital tissue.…”