Population pharmacokinetics of the 11 beta-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 in healthy volunteers following single and multiple dose regimens

作者：An Guohua^*; Liu Wei; Katz David A; Marek Gerard J; Awni Walid; Dutta Sandeep

来源：Biopharmaceutics & Drug Disposition, 2014, 35(7): 417-429.

DOI：10.1002/bdd.1912

• ABT-384
• 11 beta-hydroxysteroid dehydrogenase type 1 inhibitor
• population pharmacokinetics
• nonlinear pharmacokinetics

ABT-384 is a potent and selective inhibitor of 11-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 240mg) and multiple-dose studies (1, 2, 4, 8, 20, 30 and 100mg once daily). Less than dose-proportional pharmacokinetics of ABT-384 was observed when ABT-384 was administered at single doses lower than 8mg. 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.

• 出版日期2014-10