%0 Journal Article %A Guohua An %A Wei Liu %A David A. Katz %A Gerard Marek %A Walid Awni %A Sandeep Dutta %T 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 %D 2013 %R 10.1124/dmd.112.049742 %J Drug Metabolism and Disposition %P 1035-1045 %V 41 %N 5 %X 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. %U https://dmd.aspetjournals.org/content/dmd/41/5/1035.full.pdf