Background
Suboptimal adherence to antiretroviral therapy (ART) remains a key barrier to sustained viral suppression. Tenofovir (TFV), a cornerstone of ART, has emerged as objective biomarker of adherence through quantification of its active metabolite, tenofovir diphosphate (TFV-DP), which has long half-life. However, thresholds defining optimal adherence remain unclear, and lower TFV-DP concentrations have been observed in South African (SA) populations despite similar adherence. This study aimed to (1) develop a population pharmacokinetic (popPK) model of plasma TFV, (2) link plasma TFV to intracellular TFV-DP, and (3) explore covariates influencing drug exposure to establish adherence thresholds.
Methods
Published plasma TFV model was adapted and fitted to data from the UTRA study in SA, including people with HIV receiving 300 mg daily tenofovir disoproxil fumarate (TDF). Plasma TFV concentrations were quantified at 6- and 12-months using LC-MS/MS. NONMEM with PsN and Pirana supported analysis. Covariates of interest included age, sex, BMI, creatinine clearance (CRCL), ethnicity, and concomitant drugs.
Results
Data included 185 plasma TFV concentrations from 120 participants. Median age was 44 years (IQR 18–66), 35% male, median weight was 69.4 kg (IQR 44–132), BMI 27 kg/m² (IQR 22–35), and median CRCL 107 mL/min (IQR 54.2–336). A two-compartment model with first-order elimination best described the data (Figure 1). Absorption rate (3.04 h⁻¹), clearance (44.7 L/h), central volume of distribution (Vd, 378 L), intercompartmental clearance (157 L/h), and peripheral Vd (356 L) were all fixed. Relative bioavailability was fixed at 1 with scaling factor of 0.642 (conversion of TFV from TDF). Between-subject variability and between-occasion variability were all fixed from adapted study. Residual proportional error was 62.8%.
Conclusion
A published two-compartment model adequately described plasma TFV in this SA cohort. Future work will link plasma TFV to intracellular TFV-DP, quantify covariate effects on exposure, and establish adherence thresholds.
References
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- Kawuma AN, Wasmann RE, Sinxadi P, Sokhela SM, Chandiwana N, Venter WD, Wiesner L, Maartens G, Denti P. Population pharmacokinetics of tenofovir given as either tenofovir disoproxil fumarate or tenofovir alafenamide in an African population. CPT Pharmacometrics Syst Pharmacol. 2023;12(6):821–830.
