Population pharmacokinetics of ritonavir-boosted saquinavir regimens in HIV-infected individuals.
OBJECTIVE
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.
Dickinson
Laura
L
NIHR National Biomedical Research Centre, Royal Liverpool and Broadgreen University Hospital Trust, Liverpool, UK.
Boffito
Marta
M
Back
David J
DJ
Khoo
Saye H
SH
Pozniak
Anton L
AL
Mugyenyi
Peter
P
Merry
Concepta
C
Autar
Reshma Saskia
RS
Burger
David M
DM
Aarons
Leon J
LJ
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D005260:Female; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008962:Models, Theoretical; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019258:Saquinavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044967:Serum / Q000737:chemistry; D013785:Thailand; D014454:Uganda; D006113:United Kingdom
D019380:Anti-HIV Agents; D019258:Saquinavir; D019438:Ritonavir