Population Pharmacokinetics of Ritonavir-boosted Saquinavir Regimens in HIV-infected Individuals

Overview

Journal J Antimicrob Chemother

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2008 Oct 1

PMID 18824460

Citations 3

Authors

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

Affiliations

Soon will be listed here.

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 approximately 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.

Citing Articles

Factors affecting antiretroviral pharmacokinetics in HIV-infected women with virologic suppression on combination antiretroviral therapy: a cross-sectional study.

Loutfy M, Walmsley S, Klein M, Raboud J, Tseng A, Blitz S BMC Infect Dis. 2013; 13:256.

PMID: 23732043 PMC: 3679788. DOI: 10.1186/1471-2334-13-256.

The rainbow cohort: 96 week follow-up of saquinavir-containing regimens in previously antiretroviral therapy (ART)-naive and pre-treated but protease inhibitor (PI)-naive HIV-infected patients.

Knechten H, Stephan C, Mosthaf F, Jaeger H, Carganico A, Lutz T Eur J Med Res. 2011; 16(3):93-100.

PMID: 21486721 PMC: 3352211. DOI: 10.1186/2047-783x-16-3-93.

Cytochrome P450 3A inhibition by atazanavir and ritonavir, but not demography or drug formulation, influences saquinavir population pharmacokinetics in human immunodeficiency virus type 1-infected adults.

von Hentig N, Lotsch J Antimicrob Agents Chemother. 2009; 53(8):3524-7.

PMID: 19528289 PMC: 2715593. DOI: 10.1128/AAC.00025-09.

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