Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection

Abstract

Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h(-1) (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.

FIG. 1.

Goodness-of-fit plots of the final model for atazanavir. The heavy broken lines are smoothed plots of the ordinate values. (A) A log-log plot of observed concentrations versus population predictions; the dotted line is the line of identity. (B) A log-log plot of observations versus individual predictions; the dotted line is the line of identity. (C) Population residuals versus population predictions; the dotted line is at the ordinate value of 0. (D) Population weighted residuals versus population predictions; the dotted line is at the ordinate value of 0. (E) Plasma concentrations in 136 HIV patients (circles) receiving atazanavir at 300 mg once daily, boosted with ritonavir, with the average population prediction (solid line) and a 95% prediction interval (dashed lines) shown.

FIG. 2.

Goodness-of-fit plots of the validation model for atazanavir. The heavy broken lines are smoothed plots of the ordinate values. (A) Observed concentrations versus population predictions; the dotted line is the line of identity. (B) Observations versus individual predictions; the dotted line is the line of identity. (C) Population residuals versus population predictions; the dotted line is at the ordinate value of 0.