Journal article
Population pharmacokinetics of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 in healthy volunteers following single and multiple dose regimens
Biopharmaceutics & drug disposition, Vol.35(7), pp.417-429
10/2014
DOI: 10.1002/bdd.1912
PMID: 25041811
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.
Details
- Title: Subtitle
- Population pharmacokinetics of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 in healthy volunteers following single and multiple dose regimens
- Creators
- Guohua An - Department of Clinical Pharmacology and Pharmacometrics, R&D, AbbVie Inc., North Waukegan Road North Chicago, IL 60064, USAWei LiuDavid A KatzGerard J MarekWalid AwniSandeep Dutta
- Resource Type
- Journal article
- Publication Details
- Biopharmaceutics & drug disposition, Vol.35(7), pp.417-429
- Publisher
- England
- DOI
- 10.1002/bdd.1912
- PMID
- 25041811
- ISSN
- 0142-2782
- eISSN
- 1099-081X
- Grant note
- DOI: 10.13039/100006483, name: AbbVie
- Language
- English
- Date published
- 10/2014
- Academic Unit
- Epidemiology; Pharmaceutical Sciences and Experimental Therapeutics; General Internal Medicine; Internal Medicine
- Record Identifier
- 9984065310202771
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