Pharmacogenetics-based population pharmacokinetic analysis for dose optimization of ritonavir-boosted atazanavir in Thai adult HIV-infected patients

Background: This population pharmacokinetic-pharmacogenetic study aimed to investigate the optimal dose of RTV-boosted ATV (ATV/RTV) for Thai adult HIV-infected patients. Methods: A total of 1460 concentrations of ATV and RTV from 544 patients receiving an ATV/RTV-based regimen were analyzed. The CYP3A5 6986 A > G, ABCB1 3435 C > T, ABCB1 2677 G > T, SLCO1B1 521 T > C, and NR1l2 63396 C > T were genotyped. A population pharmacokinetic model was performed using a nonlinear mixed-effect model (NONMEM (R)). Monte Carlo simulations were conducted to compare the percentages of patients achieving the therapeutic range of ATV through concentrations (C-trough). Results: The apparent oral clearance of ATV (CL/F-ATV) without RTV was 7.69 L/h with interindividual variability (IIV) of 28.7%. Patients with CYP3A5 6986 GG had a 7.1% lower CL/F-ATV than those with AA or AG genotype. The CL/F-ATV decreased by 10.8% for females compared with males. Simulation results showed higher percentages (similar to 70%) of patient receiving doses of 200/100 or 200/50 mg achieved the target ATV C-trough, while more patients (similar to 40%) receiving a standard dose (300/100 mg) had ATV C-trough above this target. Conclusions: Both CYP3A5 6986 A > G and female decreased CL/F(ATV )in Thai HIV-infected patients. Simulations supported that the reduced dose of ATV/RTV was sufficient to achieve the target concentration for Thai population.