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Population pharmacokinetic analysis of rimonabant in healthy subjects
Author(s) -
Ferron G.M.,
Grandison M.,
Lockwood G.
Publication year - 2005
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.2004.12.058
Subject(s) - rimonabant , pharmacokinetics , medicine , pharmacology , population pharmacokinetics , population , environmental health , agonist , receptor , cannabinoid receptor
Background The purpose of this analysis was to investigate the influence of dose and key demographic parameters on the population pharmacokinetics (PPK) of rimonabant. Methods PK data were combined from 7 similar phase I studies consisting of 141 young healthy subjects (3874 observations), including 52 Japanese, 89 non Japanese, 8 female, 133 male, obese and non obese[body mass index (BMI): 18.2 ‐ 41.6 kg/m 2 , body weight: 50.4 ‐ 135 kg] and doses of 3 to 120 mg. Subjects received either a single dose or once‐daily doses for 21 days of rimonabant. The PPK model was developed using a non‐linear mixed effect model (WinNonMix, v2.0.1). Model verification was performed by an examination of the goodness of fit plots, mean weighted residuals and by estimation of the prediction error and its 95% confidence interval. Results Rimonabant PPK was described by a two‐compartment model in terms of volume (Vc/F and Vp/F) and clearance (CL/F and CLd/F) parameters with a first‐order absorption rate constant (ka) and a lag time (t lag ). Individual parameter values were log‐normally distributed. The final model included significant relationship between BMI and Vp/F, between rimonabant dose and ka, Vc/F, CL/F, and Vp/F, and between dose regimen and t lag . No effect of race was observed. Conclusions BMI appears to be the major determinant of rimonabant PK within the doses used in phase III trials, reflecting extensive distribution in the peripheral target tissues. Clinical Pharmacology & Therapeutics (2005) 77 , P43–P43; doi: 10.1016/j.clpt.2004.12.058