Population Pharmacokinetics of Atazanavir in HIV-infected Patients
C Solas (1), MC Gagnieu (2), I Ravaux (3), MP Drogoul (4), A Lafeuillade (5), S Mokhtari (6), B Lacarelle (1) and N Simon (1).
(1) Fédération de Pharmacologie, Hôpital Timone, Marseille, France, (2) Laboratoire de Pharmacologie, Hôpital Edouard Herriot, Lyon, France, (3) Service de maladies infectieuses, Hôpital Conception, Marseille, France, (4) CISIH, Hôpital Sainte-Marguerite, Marseille, France, (5) Service de maladies infectieuses, Hôpital Chalucet, Toulon, France, (6) Service de maladies infectieuses, Hôpital Nord, Marseille, France
Objectives: The aim of the study was to determine the main pharmacokinetic (PK) parameters of ATV in real life using a population PK approach in HIV infected patients treated with the once daily association ATV/ritonavir.
Methods: Observational study in patients treated with the once-daily regimen ATV associated to 100 mg of ritonavir. Blood samples were drawn at steady state, at various time ranging from 1 to 26 hours post dose. ATV plasma concentrations were determined by a HPLC method. ATV population PK analysis was performed using a non linear mixed-effects model (NONMEM version 6).
Results: One hundred and eighty seven patients with a median age of 41 years were included during the follow-up period. The ATV doses prescribed were 300 mg (n=169), 400 mg (n=12), 200 mg (n=1) and 150 mg (n=5). ATV population PK was described using a one-compartment model with first order absorption. Mean PK parameters estimations (inter-subject variability, %) were as follow: oral clearance (CL) = 7.63 L/h (34), volume of distribution (V) = 80.8 L (37) and constant of absorption (KA) = 1.05 h-1 (156). The introduction of a lag time significantly improved the fit. The random residual variability was 522 ng/ml (standard error= 156). The mean estimated half-life (T-half) was 7.5 hours.
Conclusion: Estimated T-half of ATV in 187 HIV-infected patients in the context of real life was comparable to that previously reported of 8.8 h on a larger population (n=214) and 8.6 h in a small study involving 10 HIV-infected patients. We observed a wide interpatient variability in the ATV clearance, volume of distribution and constant of absorption. Because of its once-daily administration, the ATV Ctrough samples may not always be collected accurately, particularly in patients taking ATV in the evening. This model may be useful, using Bayesian method, to predict ATV Ctrough from plasma samples collected anytime during the dosing interval.