Journal article
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
Drug metabolism and disposition, Vol.41(5), pp.1035-1045
05/2013
DOI: 10.1124/dmd.112.049742
PMID: 23431112
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.
Details
- Title: Subtitle
- 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
- Creators
- Guohua An - Department of Pharmaceutics, University of Florida, 6550 Sanger Road, Orlando, FL 32827, USA. guohuaan@cop.ufl.eduWei Liu - AbbVieDavid A KatzGerard MarekWalid AwniSandeep Dutta
- Resource Type
- Journal article
- Publication Details
- Drug metabolism and disposition, Vol.41(5), pp.1035-1045
- Publisher
- United States
- DOI
- 10.1124/dmd.112.049742
- PMID
- 23431112
- ISSN
- 0090-9556
- eISSN
- 1521-009X
- Language
- English
- Date published
- 05/2013
- Academic Unit
- Epidemiology; Pharmaceutical Sciences and Experimental Therapeutics; General Internal Medicine; Internal Medicine
- Record Identifier
- 9984065503002771
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