Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients

Abstract

Limited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13. ؊1 ; P ‫؍‬ 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.

Pharmacokinetics of Unboosted Atazanavir in Treatment-experienced HIV-infected Children, Adolescents and Young Adults

“…It was suggested that an unboosted ATV daily dose of 900 mg would be required for subjects >13 years old and 475 mg for subjects 6–13 years old. Our data support the need for a much higher dose than is currently recommended as both the ATV 400 and 600 mg dose in our study produced exposures in adolescents and young adults below those achieved with ATV/r that achieve a good virologic response in adults (9). The impact of higher unboosted doses on the virologic efficacy in this heavily treated group is difficult to extrapolate but the safety data reported with higher ATV exposure in these children and adolescents are reassuring (6).…”

Pharmacokinetics and pharmacodynamics of cytochrome P450 inhibitors for HIV treatment

“…ATV shows an EC 50 of 2-5 nM range against HIV-1 group M subtypes (A-D, AE, AG, F, G, and J) in in vitro system. A population pharmacokinetic model, including a mixed model of absorption, suggested a significant difference in ATV pharmacokinetics, regimens, and virological failure between the patients experiencing unboosted ATV [42]. Accordingly, recommended dosing of ATV is 300 mg with RTV, a PI booster with food or only ATV 400 mg once daily with food.…”

Population pharmacokinetic modelling of the changes in atazanavir plasma clearance caused by ritonavir plasma concentrations in HIV‐1 infected patients

“…Further studies, in which food intake is controlled for, should be performed to determine the causes of high interindividual variability in ATV absorption. Reducing unexplained interindividual variability in predictive models could be of great help in clinical settings, especially considering the recent results reported by Goutelle et al , indicating that patients treated with ATV showing virological failure had lower k a values than those without failure.…”