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A population pharmacokinetic (POP PK) analysis of ritonavir (RTV) in human immunodeficiency virus‐infected patients enrolled in ACTG359
Author(s) -
Levi M.,
Brundage R. C.,
Fletcher C. V.,
Sheiner L. B.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.335
Subject(s) - pharmacokinetics , saquinavir , ritonavir , nonmem , population , pharmacology , volume of distribution , covariate , distribution (mathematics) , protease inhibitor (pharmacology) , medicine , human immunodeficiency virus (hiv) , chemistry , mathematics , antiretroviral therapy , statistics , viral load , virology , mathematical analysis , environmental health
The protease inhibitor (PI) RTV was used in ACTG359 as a metabolic inhibitor to increase saquinavir (SQV) concentrations, and also to contribute to virologic efficacy. HIV‐positive patients (99) were administered SQV and RTV (both 400 mg bid). Intensive PK samples were taken from a subset (18) and random concentrations were obtained from all patients. A one‐compartment disposition PK model with input via a catenary chain of four absorption compartments (a new modeling feature for this drug) was fit to the data. RTV pop PK parameters were estimated, as were MAP Bayes estimates of each individual's oral clearance (CL/F) and the ratio of the posterior variance of this estimate to its prior variance (PVR). This ratio is reciprocally proportional to the amount of information supplied by all PK observations in the individual. Pop PK estimates are: CL/F = 7.4 L/h, consistent with previous studies; volume of distribution = 59.7 L; mean absorption time = 3.25 h. The catenary chain absorption sub‐model was necessary to fit the slow sigmoidal ascent to peak RTV concentration, and may prove useful in other cases of delayed peak concentrations of PIs. PVRs were considerably higher for individuals with only sparse samples than for those intensively sampled, providing a means to weight CL/F as a covariate for exposure‐response regressions. Clinical Pharmacology & Therapeutics (2004) 75 , P88–P88; doi: 10.1016/j.clpt.2003.11.335