title: Population pharmacokinetics of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 in healthy volunteers following single and multiple dose regimens.
abstract: ABT-384 is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). The pharmacokinetics of ABT-384 was evaluated in healthy volunteers in single-dose (1, 8, 20, 50, 120 and 240 mg) and multiple-dose studies (1, 2, 4, 8, 20, 30 and 100 mg once daily). Less than dose-proportional pharmacokinetics of ABT-384 was observed when ABT-384 was administered at single doses lower than 8 mg. This nonlinear phenomenon disappeared after repeated doses. The dose-normalized plasma concentration-time curves superposed across all dose groups on day 7, but not on day 1. This phenomenon cannot be explained by the half-life of ABT-384. Based on available data, the nonlinearity is likely due to binding of ABT-384 to a high-affinity-low-capacity site, such that this interaction was reflected in ABT-384 pharmacokinetics. To characterize the pharmacokinetics of ABT-384, a population pharmacokinetic model for ABT-384 was constructed. The model provided reasonable fitting for both single- and multiple-dose data. Further investigation is warranted to evaluate the disposition of ABT-384 at low doses using a larger number of subjects. The constructed model would be useful in predicting ABT-384 concentrations at different doses and guiding the selection of dosing regimens in further clinical trials.
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, R&D, AbbVie Inc., North Waukegan Road North Chicago, IL 60064, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: An
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: David A
authors.initials: DA
authors.lastname: Katz
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Marek
authors.forename: Walid
authors.initials: W
authors.lastname: Awni
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000097:blood*; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C584004:N-(5-(aminocarbonyl)tricyclo(3.3.1.13,7)dec-2-yl)-alpha,alpha-dimethyl-4-(5-(trifluoromethyl)-2-pyridinyl)-1-piperazineacetamide; D010879:Piperazines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane
keywords: 11β-hydroxysteroid dehydrogenase type 1 inhibitor; ABT-384; nonlinear pharmacokinetics; population pharmacokinetics