Population Pharmacokinetics (PPK) and Pharmacokinetic-Pharmacodynamic (PK/PD) of Vicriviroc in Treatment Naive HIV
C. Xu(1), H. Zhou(2), G. Krishna(1), M. McCarthy(3).
(1) Clinical PK/PD, Department of Drug Metabolism and Pharmacokinetics, (2) BARDS, (3) Global Clinical Research, Merck Research Labs, USA
Objectives: Vicriviroc is a potent CCR5 antagonist for treating HIV-1 infection. This study aimed to (1) assess vicriviroc pharmacokinetic (PK) profile and interpatient versus intrapatient variability in HIV positive patients using PPK, and (2) to explore PK/PD association using drug exposure and efficacy.
Methods: This global Phase 2 trial explored a class-sparing regimen of vicriviroc, a CCR5 antagonist vs Truvada, each in combination with ritonavir-boosted atazanavir (ATV/r). CCR5 HIV-infected treatment-naïve subjects were randomized 1:1 to open-label treatments with 95 and 123 subjects in Stage 1 and 2, respectively. The PPK analysis was performed using NONMEM based on plasma samples from patients receiving vicriviroc. Two plasma samples were collected pre-dose and approximately 1 hr post-dose on Weeks 4 and 12. Since the sparse PK sampling scheme was utilized in this Phase 2 trial, PK data from Phase I studies were combined and used for the population PK analysis. The influence of demographic and clinical characteristics on clearance and volume of distribution were examined. The drug exposure (AUC, Cmin and Cmax) was estimated for each patient and the exposure-virologic response association was explored.
Results: 105 vicriviroc treated patients contributed to 402 vicriviroc concentrations. Two-compartment model with first-order absorption and elimination was chosen as the pharmacokinetic base model. The apparent clearance (CL/F) was 3.39 L/h, apparent volume of distribution of the central compartment (Vc/F) was 170 L and the absorption rate constant (Ka) was 0.743 hr-1. Of the covariates evaluated, body weight was a significant covariate for CL/F and age was a significant covariate for Vc/F. A large interpatient variability was found for Ka (CV 70%), while the intrapatient variability was relatively small (CV 19%). The final model was evaluated by the bootstrap technique and the visual predictive check. The correlation between trough drug concentration (Cmin) and viral load change was assessed. Despite 99% patients has vicriviroc Cmin greater than 100 ng/mL, higher response rates were observed in naive subjects with higher vicriviroc Cmin.
Conclusions: A two-compartment model adequately described the vicriviroc PK in naïve HIV patients. Body weight and age were significant covariates. The integrated population PK model and PK-PD association can be used to predict antiviral activity and select the optimal dose regimen in naive patients.