title: Effect of ketoconazole on the pharmacokinetics of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 and its two active metabolites in healthy volunteers: population analysis of data from a drug-drug interaction study.
abstract: ABT-384 [1-piperazineacetamide, N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-,stereoisomer] is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). ABT-384 has been shown to be safe and well tolerated in humans at doses up to 100 mg daily, and to fully inhibit both peripheral and brain HSD-1 at a dose of 2 mg daily. The effect of ketoconazole on the pharmacokinetics of ABT-384 and its two active metabolites, A-1331480 and A-847082, was investigated in healthy volunteers. When 10 mg of ABT-384 was coadministered with ketoconazole, ABT-384 exposures increased 18-fold for area under the plasma concentration-time curve from time 0 to infinity and 3.5-fold for Cmax. The results suggest that ABT-384 is a sensitive substrate of CYP3A. After ketoconazole coadministration, exposures of A-1331480 and A-847082 were also greatly increased. A population pharmacokinetic model was constructed for ABT-384 and its metabolites using NonMEM. A two-compartment model with three transit absorption compartments best described ABT-384 data. The model predicted a 69.3% decrease in ABT-384 clearance and 91.1% increase in the volume of distribution of ABT-384 in the presence of ketoconazole. A-1331480 was shown to be formation rate-limited and A-847082 was elimination rate-limited. Both metabolites were characterized by a one-compartment model with first-order rate constants of formation and elimination. Overall the model adequately captured the concentration-time profiles of ABT-384, A-1331480, and A-847082 in both ABT-384-alone and ketoconazole-coadministration conditions. Although ABT-384 exposures were greatly increased in the presence of ketoconazole, coadministration of ABT-384 with ketoconazole or other strong/moderate CYP3A inhibitors is not expected to contribute to any major clinical safety issues considering the favorable safety profile of ABT-384.
authors: Department of Pharmaceutics, University of Florida, 6550 Sanger Road, Orlando, FL 32827, USA. guohuaan@cop.ufl.edu
authors: Guohua
authors: G
authors: An
authors: Wei
authors: W
authors: Liu
authors: David A
authors: DA
authors: Katz
authors: Gerard
authors: G
authors: Marek
authors: Walid
authors: W
authors: Awni
authors: Sandeep
authors: S
authors: Dutta
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008962:Models, Theoretical; D010879:Piperazines / Q000493:pharmacokinetics*; D012016:Reference Values
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; 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; D007654:Ketoconazole