Population pharmacokinetic modelling to characterize the effect of chronic kidney disease on tenofovir exposure after tenofovir alafenamide administration.  Journal of Antimicrobial Chemotherapy
Thoueille et al. aimed to describe tenofovir pharmacokinetics (PK) and its variability in people living with HIV (PLWH) under tenofovir alafenamide in a real-life setting.
The authors conducted a population PK analysis (NONMEM®) on 877 tenofovir and 100 tenofovir alafenamide concentrations measured in 569 PLWH. Model-based simulations allowed prediction of tenofovir trough concentrations (Cmin) in patients having various levels of renal function.
Tenofovir PK was best described using a one-compartment model with linear absorption and elimination. Creatinine clearance (CLCR, estimated according to Cockcroft and Gault), age, ethnicity and potent P-glycoprotein inhibitors were statistically significantly associated with tenofovir clearance. However, only CLCR appeared clinically relevant. Model-based simulations revealed 294% and 515% increases of median tenofovir Cmin in patients with CLCR of 15–29 mL/min (CKD stage 3), and less than 15 mL/min (stage 4), respectively, compared with normal renal function (CLCR = 90–149 mL/min). Conversely, patients with augmented renal function (CLCR > 149 mL/min) had a 36% decrease of median tenofovir Cmin.
In conclusion, this study demonstrates that CLCR is the main factor affecting circulating tenofovir exposure after tenofovir alafenamide administration. The proposed model reveals that patients with stage 3 and stage 4 CKD reach plasma tenofovir exposure of the same order as patients with normal kidney function receiving tenofovir disoproxil fumarate. A dosage adaptation to one-half and one-third of the standard tenofovir alafenamide regimen seems reasonable in patients with stage 3 and 4 CKD, respectively. A prospective validation of these suggestions regarding tenofovir alafenamide dosing intervals as a function of CKD remains warranted.