A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine

Abstract

Background: A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic (PK) data and mathematical modeling to determine the number of doses required for effective human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP).

Methods: A PK/pharmacodynamic (PD) model was developed by measuring mucosal tissue concentrations of tenofovir, emtricitabine, their active metabolites (tenofovir diphosphate [TFVdp] and emtricitabine triphosphate [FTCtp], respectively), and competing endogenous nucleotides (dATP and dCTP) in 47 healthy women. TZM-bl and CD4(+) T cells were used to identify 90% effective concentration (EC90) ratios of TFVdp to dATP and FTCtp to dCTP (alone and in combination) for protection against HIV. Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract and colorectal tissues.

Results: The colorectal TFVdp concentration was 10 times higher than that in the lower female genital tract, whereas concentrations of endogenous nucleotides were 7-11 times lower. Our model predicted that ≥98% of the population achieved protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate plus emtricitabine. However, a minimum adherence to 6 of 7 doses/week (85%) was required to protect lower female genital tract tissue from HIV, while adherence to 2 of 7 doses/week (28%) was required to protect colorectal tissue.

Conclusions: 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.

Keywords: HIV; antiretroviral; dose response; population pharmacokinetics-pharmacodynamics; preexposure prophylaxis; quantitative pharmacology; translational medicine.

Figure 1.

Dose proportionality in blood plasma, peripheral blood mononuclear cells (PBMCs), and mucosal tissues. Mean (±standard error) areas under curve over 48 hours (AUC_0–48h) for tenofovir (TFV; A), TFV diphosphate (TFVdp; B), emtricitabine (FTC; C), and FTC triphosphate (FTCtp; D) in female genital tract (FGT) tissue (Δ), colorectal tissue (○), and plasma (□) for tenofovir and emtricitabine and in PBMCs for TFVdp and FTCtp (□).

Figure 2.

Tissue endogenous nucleotide concentrations plotted as median values (solid line within each box), 25th and 75th percentiles (box edges), and 10th to 90th percentiles (whiskers) for 47 women. *P < .05. A, Median deoxyadenosine triphosphate (dATP) concentrations are 85% lower in colorectal tissue, compared with cervical and vaginal tissues (P < .05; n = 47). B, Median deoxycytidine triphosphate (dCTP) concentrations in colorectal tissue are 90% lower than those in cervical tissue and 80% lower than those in vaginal tissue (P < .001; n = 47).

Figure 3.

In vitro concentration versus response for TZM-bl cells and CD4⁺ T cells. TZM-bl and stimulated, primary CD4⁺ T cells were incubated for 24 hours in 0.03–35 µM concentrations of tenofovir and emtricitabine. Intracellular active metabolite and endogenous nucleotide (EN) concentrations were quantified at the time of challenge with human immunodeficiency virus type 1 (HIV-1_JR-CSF; for TZM-bl cells) or pseudovirus with HIV-1_JR-CSF envelope (for CD4⁺ T cells). For TZM-bl cells, 34 samples were collected for tenofovir diphosphate (TFVdp):deoxyadenosine triphosphate (dATP) measurement and 41 for emtricitabine triphosphate (FTCtp):deoxycytidine triphosphate (dCTP) measurement across at least 2 independent experiments (values in 6 of 72 samples were below the limit of quantification [BLQ]). For CD4⁺ T cells, 14 samples were collected for TFVdp:dATP measurement and 27 for FTCtp:dCTP measurement across at least 2 independent experiments (values in 2 of 42 samples were BLQ). Solid lines represent the median regression line of the E_max model. The dashed reference line indicates 90% inhibition of human immunodeficiency virus (HIV) infection, and the dotted line represents 50% inhibition. The 50% effective concentration (EC₅₀) ratio (±standard error [SE]) for TFVdp:dATP (A) was 0.010 ± 0.001 (P < .001), with a Hill slope (±SE) of 1.02 ± 0.09 (P < .001) in TZM-bl cells (○) and 0.086 ± 0.011 (P < .001) with a Hill slope of 1.81 ± 0.39 (P < .001) in CD4⁺ T cells (▴). B, The EC₅₀ ratio (±SE) for FTCtp:dCTP was 0.059 ± 0.004 (P < .001) with a Hill slope (±SE) of 1.42 ± 0.11 (P < .001) in TZM-bl cells (○) and 0.022 ± 0.005 (P < .001) with a Hill slope of 1.88 ± 0.67 (P < .05) in CD4⁺ T cells (▴).

Figure 4.

Time to protection and minimally effective preexposure prophylaxis (PrEP) dosing. Shown are pharmacokinetic (PK)/pharmacodynamic (PD) simulations for colorectal tissue (A and B) and lower female genital tract (FGT) tissue (C and D). A and C, The percentage of the simulated population achieving the 90% effective concentration (EC₉₀) for tenofovir diphosphate (TFVdp):deoxyadenosine triphosphate (dATP), emtricitabine triphosphate (FTCtp):deoxycytidine triphosphate (dCTP), or combination ratios derived from the in vitro PK/PD relationship in CD4⁺ T cells is plotted over the dosing interval for the first 10 daily doses of tenofovir disoproxil fumarate (TDF; dashed line), emtricitabine (FTC; dotted line), or the fixed-dose combination (TDF plus FTC; solid line). B and D, The percentage of the population achieving these EC₉₀ ratios at the end of the dosing interval under steady-state conditions with 1–7 doses/week of TDF, FTC, or TDF plus FTC are stratified by tissue. We predict that the maximal percentage of the population achieved EC₉₀ ratios by the third daily dose of TDF plus FTC in colorectal and FGT tissues after beginning PrEP. Consistently using 7 doses/week of TDF plus FTC will achieve EC₉₀ ratios in 100% of the population in FGT and colorectal tissues. Only 65% of the population using 2 doses/week of TDF plus FTC achieve target exposure in the FGT tissue, whereas ≥95% using 2 doses/week of either TDF or TDF plus FTC achieve target exposure in colorectal tissue.

Figure 5.

Protection with pericoital preexposure prophylaxis (PrEP) dosing. Shown are pharmacokinetic (PK)/pharmacodynamic (PD) simulations for the Ipergay dosing regimen (2 tablets 2–24 hours before coitus [solid vertical line], 1 tablet 24 hours after coitus, and 1 tablet 48 hours after coitus) for tenofovir disoproxil fumarate (TDF; solid line) and the fixed-dose combination of TDF plus emtricitabine (FTC; dashed line). The percentage of the simulated population achieving the 90% effective concentration (EC₉₀) of tenofovir diphosphate (TFVdp):deoxyadenosine triphosphate (dATP), with or without FTC triphosphate (FTCtp):deoxycytidine triphosphate (dCTP), derived from the in vitro PK/PD relationship in CD4⁺ T cells over 14 days following a single act of coitus in colorectal (A and B) and lower female genital tract (FGT) tissue (C and D). PK/PD simulations are reported on the assumption that the first dose was administered 24 hours (A and C) or 2 hours (B and D) before coitus. We predict the maximal percentage of the population achieving EC₉₀ ratios in colorectal tissue over a 240-hour postcoital window is achieved by initiating the Ipergay dosing 24 hours before coitus. Dosing at 24 hours or 2 hours before coitus did not appear to alter the percentage of the population achieving target exposure in the FGT tissue over a 72-hour postcoital window.