This model is predictive of recent PrEP trial results in which 2-3 doses/week was 75%-90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.

NCT00775294.

Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected three efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and three uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). 100% of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co-medications revealed significant (p<0.05) differences in efflux transporter mRNA between tissue types (vaginal ABCB1 3.9 fold > colorectal; vaginal ABCC2 2.9 fold>colorectal; colorectal ABCC4 2.0 fold>cervical). In contrast, uptake transporter mRNA was expressed in <25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate antiretroviral selection to target these tissues.

After tenofovir alafenamide dosing in vivo , tenofovir-dp was unquantifiable in most tissues (91%) although cervical and vaginal epithelial cells efficiently formed tenofovir-dp from tenofovir alafenamide in vitro . These findings warrant further investigation of tenofovir alafenamide's pharmacology.

Objectives To describe first dose and steady-state pharmacokinetics (PK) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV negative men. Design A Phase 1, open label, PK study that enrolled 12 healthy men taking DTG 50mg daily for 8d. Methods Eleven paired BP samples and 3 SF and RF samples were collected over 24h following first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated LC-MS/MS. Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3 and Spearman Rank Correlations determined using SAS v9.3. Results BP AUCs were similar to previous reports and C24h was 6 - 34 fold greater than the protein adjusted (PA) IC90 of 64 ng/mL. SF exposures were ∼7% of BP, and below the PA-IC90. RT exposures were 17% of BP and ∼2-fold greater than PA-IC90. RF AUCs were ∼2-5% of RT and did not correlate with RT (Rho =0.43, p=0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT. Conclusions DTG BP PK were consistent with previously published values. SF concentrations were <7% BP, with SF C24h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24h remained ∼ 2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.