Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist
Journal Title: The AAPS Journal - Year 2010, Vol 12, Issue 4
Abstract
Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence of selected covariates. Data from 12 phase 1 studies and one phase 2 study were pooled from subjects administered single and multiple oral doses of taranabant ranging from 0.5 to 8 mg. A total of 6,834 taranabant plasma concentrations from 187 healthy and 385 obese subjects were used to develop the population model in NONMEM. A standard covariate analysis using forward selection (α = 0.05) and backward elimination (α = 0.001) was conducted. A three-compartment model with first-order absorption and elimination adequately described plasma taranabant concentrations. The population mean estimates for apparent clearance and apparent steady-state volume of distribution were 25.4 L/h and 2,578 L, respectively. Statistically significant covariate effects were modest in magnitude and not considered clinically relevant (the effects of body mass index (BMI) and creatinine clearance (CrCL) on apparent clearance; BMI, age, CrCL, and gender on apparent volume of the peripheral compartment and age on apparent intercompartmental clearance). The pharmacokinetic profile of taranabant can adequately be described by a three-compartment model with first-order absorption and elimination. Clinical dose adjustment based on covariates effects is not warranted.
Authors and Affiliations
Xiujiang (Susie) Li, Jace Nielsen, Brenda Cirincione, Hankun Li, Carol Addy, John Wagner, Alan Hartford, Ngozi Erondu, Ira Gantz, Jerry Morgan, Julie Stone
Keywords
Related Articles
- EP ID EP681417
- DOI 10.1208/s12248-010-9212-2
- Views 71
- Downloads 0
Harmonization of Regulatory Approaches for Evaluating Therapeutic Equivalence and Interchangeability of Multisource Drug Products: Workshop Summary Report
Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo b...
Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers
Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling networks by terminating signals produced by active Gα subunits. RGS17, a member of the RZ subfamily of RGS pro...
A critical review of analytical ultracentrifugation and field flow fractionation methods for measuring protein aggregation
Analytical ultracentrifugation (AUC) and field flow fractionation (FFF) are 2 important biophysical methods for measuring protein aggregates. Both methods can separate protein monomer from its aggregate forms under a bro...
Delivery of siRNA Therapeutics: Barriers and Carriers
RNA interference is a naturally occurring endogenous regulatory process where short double-stranded RNA causes sequence-specific posttranscriptional gene silencing. Small interference RNA (siRNA) represents a promising t...
International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences
The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug product...