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

Biopharm Drug Dispos. 2014 Oct;35(7):417-29. doi: 10.1002/bdd.1912. Epub 2014 Aug 30.

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.

Keywords: 11β-hydroxysteroid dehydrogenase type 1 inhibitor; ABT-384; nonlinear pharmacokinetics; population pharmacokinetics.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / blood*
  • Adamantane / administration & dosage
  • Adamantane / analogs & derivatives*
  • Adamantane / blood
  • Adamantane / pharmacokinetics
  • Adult
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Healthy Volunteers
  • Humans
  • Male
  • Middle Aged
  • Piperazines / administration & dosage*
  • Piperazines / blood*
  • Piperazines / pharmacokinetics
  • Young Adult

Substances

  • N-(5-(aminocarbonyl)tricyclo(3.3.1.13,7)dec-2-yl)-alpha,alpha-dimethyl-4-(5-(trifluoromethyl)-2-pyridinyl)-1-piperazineacetamide
  • Piperazines
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Adamantane