Panhard X (1), Legrand M (1), Taburet AM (2), Diquet B (3), Goujard C (2), Mentré F (1) and the Cophar 1 – ANRS 102 study group
(1) INSERM U738, AP-HP, Paris ; (2) Bicetre Hospital, AP-HP, Le Kremlin Bicetre ; (3) CHU, Angers, France
Objectives: Little is known about pharmacokinetic (PK) characteristics of combined nucleoside analogs (NA) in patients (pts) treated with HAART. Our objectives were 1/ to build a population pharmacokinetic model of ZDV, LMV and STV 2/ to estimate their inter-individual PK variability and 3/ to investigate the influence of different covariates.
Methods: The Cophar-1 study was a prospective, open, multicenter trial including pts with unchanged HAART containing either indinavir (IDV) or nelfinavir (NFV), and with a sustained virological response (viral load <200 RNA copies/mL) since the last 4 months. The primary objective was to study IDV and NFV PK within blood samples taken before and 0.5, 1, 3, 6 and 12 hours after dosing. As a secondary objective, NA concentrations were measured in plasma. 95 patients were included, 88 had a sustained virological response for 8 months of follow-up and were analysed: 54, 39 and 27 received LMV, STV or ZDV, respectively. A one compartment model with first order elimination was used to describe NA concentrations, with a zero order absorption parametrized in duration of absorption (Tabs) for LMV and a first order absorption parametrized in absorption rate constant (ka) for STV and ZDV. The influence of covariates (age, weight, sex, creatinine clearance, adherence) and of combined antiretroviral drugs (NFV or IDV) was tested. The data were modelled using a population approach (function nlme of the R software), with exponential random effects and a constant variance error model.
Results: Mean parameters (CV%) of LMV, STV and ZDV were respectively: oral volume of distribution (V/F) 143L (49%), 24 L (82%) and 194 L (88%), oral clearance (Cl/F) 31 L/h, 21 L/h (77%) and 121 L/h (49%). For LMV, Tabs was 1.15 h (62%). For STV and ZDV, ka was 0.46 h-1 and 2.8 h-1, respectively. The only significant covariate effect was combination with NFV vs IDV. In pts receiving NFV, Tabs of LMV is divided by 1.4 (p=0.002), Cl/F of STV is multiplied by 1.6 (p=0.001) and both V/F (p<0.0001) and Cl/F (p=0.001) of ZDV are multiplied by 1.5, suggesting a decrease in ZDV bioavailability when combined with NFV.
Conclusions: This trial first designed to study protease inhibitor PK also gave us an estimation of PK parameters for the combined NA. We observed for the 3 NA a great variability of PK parameters and a systematic effect of NFV. This plasma concentrations variability may have consequences on the concentrations of intracellular active metabolites and requires further investigations.
Reference: PAGE 14 () Abstr 723 [www.page-meeting.org/?abstract=723]
Poster: poster