TITLE

Population pharmacokinetics of ritonavir-boosted saquinavir regimens in HIV-infected individuals

AUTHOR(S)
Laura Dickinson; Marta Boffito; David J. Back; Saye H. Khoo; Anton L. Pozniak; Peter Mugyenyi; Concepta Merry; Reshma Saskia Autar; David M. Burger; Leon J. Aarons
PUB. DATE
December 2008
SOURCE
Journal of Antimicrobial Chemotherapy (JAC);Dec2008, Vol. 62 Issue 6, p1344
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
: Objectives The aim of this study was to develop and validate a population pharmacokinetic model in order to describe ritonavir-boosted saquinavir concentrations dosed twice and once daily in human immunodeficiency virus (HIV)-infected patients from the UK, Uganda and Thailand and to identify factors that may influence saquinavir pharmacokinetics. : Methods Pharmacokinetic data from 10 clinical studies were combined. Non-linear mixed effects modelling (NONMEM version V) was applied to determine the saquinavir pharmacokinetic parameters, interindividual/interoccasion variability (IIV/IOV) and residual error. Various covariates potentially related to saquinavir pharmacokinetics were explored, and the final model was validated by means of 95% prediction interval and testing the predictive performance of the model with data not included in the model-building process. : Results Ninety-seven patients were included from the UK (n = 52), Uganda (n = 18) and Thailand (n = 27), contributing 347 saquinavir profiles (1–14 profiles per patient). A one-compartment model with zero-order absorption and lag-time best described the data with IIV/IOV on apparent oral clearance (CL/F) and volume of distribution (V/F) and with IIV on duration and absorption lag-time. The ritonavir area under the curve over the dosing interval was significantly associated with saquinavir CL/F and V/F. A typical patient from the UK had ∼1.5- and 3-fold higher saquinavir CL/F compared with patients from Uganda (89.0 versus 49.8 L/h) and Thailand (89.0 versus 26.7 L/h), respectively. : Conclusions A model to characterize ritonavir-boosted saquinavir pharmacokinetics in HIV-infected adults has been developed and validated. The model could be used for dosage adaptation following therapeutic drug monitoring and to assess patients suitability for once-daily boosted saquinavir therapy.
ACCESSION #
35260827

 

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