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Population pharmacokinetics of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor ABT‐384 in healthy volunteers following single and multiple dose regimens
Author(s) -
An Guohua,
Liu Wei,
Katz David A.,
Marek Gerard J.,
Awni Walid,
Dutta Sandeep
Publication year - 2014
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1912
Subject(s) - pharmacokinetics , pharmacology , dosing , population , medicine , chemistry , environmental health
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. Copyright © 2014 John Wiley & Sons, Ltd.