(S-078) A Translational QSP Modeling Framework Demonstrates Tissue-Level Pharmacokinetics Do Not Predict the Clinical Efficacy of FTC/TDF PrEP

Sara Iannuzzi – Freie Universität Berlin; Malin Müller – Faculty of Science and Engineering, Maastricht University, Netherlands; Max von Kleist – Project groups, Robert-Koch Institute Berlin, Germany; Dep. of Mathematics and Computer Science, Freie Universität Berlin, Germany

Objective: Despite the ongoing spread of HIV, the development and uptake of prevention tools remains crucial. Pre-exposure prophylaxis (PrEP) with oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), denotes a widely adopted tool for self-protection. However, WHO PrEP guidelines differ for cisgender women vs. men who have sex with men (MSM). Mechanistically, the distinction is motivated by differences in tissue-level pharmacokinetics (PK) at vaginal- vs. rectal exposure sites. Building on prior findings that vaginal tissue-level pharmacokinetics do not predict prophylactic efficacy in cisgender women, this study aims to identify pharmacokinetic markers correlating with PrEP efficacy in MSM by combining mechanistic modeling with analysis of the clinical data.

Methods: In analogy to [1], we estimated ‘clinical PrEP efficacy’ ranges in MSM with quantifiable drug, from data of four major FTC/TDF-PrEP trials (IPERGAY, iPrEx, HPTN 083, PURPOSE 2). Independently, we adopted previously validated population pharmacokinetics models [2, 3] to simulate plasma-, Peripheral Blood Mononuclear Cells (PBMC)- and tissue-level pharmacokinetics. We then predicted their impact on initial viral dynamics by integrating a mechanism of action (MOA) model of direct drug effect for FTC-triphosphate (FTC-TP) and tenofovir diphosphate (TFV-DP) [4]. We then
quantitatively estimated adherence-prophylactic efficacy relationships under the assumption that either colorectal tissue or PBMC concentrations were the primary determinants of drug effect. Finally, we tested whether derived adherence-efficacy relationships using either colorectal tissue- vs. PBMCs PK were (in-)congruent with ‘clinical PrEP efficacy’ estimates. This allowed formal hypothesis testing of proposed pharmacokinetic surrogates and evaluation of the suitability of specific pharmacokinetic markers for predicting 'clinical PrEP efficacy'.

Results: Derived ‘clinical PrEP efficacy’ ranges for MSM with quantifiable drug were consistently high across trials. However, estimates from iPrEx, IPERGAY, and PURPOSE 2 were associated with greater statistical uncertainty (mean [95% CI]: 87 [70–96], 88 [33–100], and 85 [54–97], respectively), in contrast to the more precise estimate from HPTN 083 (97 [93–99]). Independent modelling using PBMCs as a drug marker revealed that >90% mean
population efficacy was achieved when MSM took PrEP at least three times per week, closely matching clinical efficacy estimates. In contrast, if colorectal tissue pharmacokinetics predicted efficacy, even fully adherent individuals may not reach 90% mean population efficacy. Statistical testing of these adherence-prophylactic efficacy profiles indicated that colorectal tissue PK does not predict ‘clinical PrEP efficacy’.

Conclusions: This study, together with earlier work [1] suggests that drug concentrations in exposed tissue neither predict prophylactic efficacy in MSM, nor cis-gender women. On the other hand, pharmacokinetics in PBMC, which are identical between the two risk groups, are congruent with ‘clinical PrEP efficacy’. Our results suggest that different PrEP efficacy in women vs. MSM may be due to differences in adherence behaviour rather than differences in adherence demands.

Citations:
[1] Zhang L, Iannuzzi S, Chaturvedula A, Irungu E, Haberer JE, Hendrix CW, et al. Model-based predictions of protective HIV pre-exposure prophylaxis adherence levels in cisgender women. Nature Medicine. 2023;29(11):2753-62.
[2] Burns RN, Hendrix CW, Chaturvedula A. Population pharmacokinetics of tenofovir and tenofovir-diphosphate in healthy women. The Journal of Clinical Pharmacology. 2015;55(6):629-38.
[3] Garrett KL, Chen J, Maas BM, Cottrell ML, Prince HA, Sykes C, et al. A pharmacokinetic/pharmacodynamic model to predict effective HIV prophylaxis
dosing strategies for people who inject drugs. Journal of Pharmacology and Experimental Therapeutics. 2018;367(2):245-713.
[4] Iannuzzi S, von Kleist M. Mathematical modelling of the molecular mechanisms of interaction of tenofovir with emtricitabine against HIV. Viruses. 2021;13(7):1354.