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- Title
An adaptive design to investigate the effect of ketoconazole on pharmacokinetics of GSK239512 in healthy male volunteers.
- Authors
Xu, Jianfeng; Hilpert, Jan; Wu, Kai; van Hecke, Benjamin; Collins, Gary; Patel, Aarti; Mohindra, Rajat; Davies, Matt J. B.; Xu, Yanmei; Thompson, Paul
- Abstract
This open label drug-drug interaction (DDI) study investigated the effect of a strong CYP3A inhibitor ketoconazole on the PK and safety profile of GSK239512. To mitigate the tolerability concerns of high GSK239512 exposures resulting from CYP3A inhibition, a 2-cohort adaptive design was used to facilitate a stepwise selection of dose levels and subject numbers. In Cohort 1, 6 subjects received a single dose of 20 μg GSK239512 alone and then 10 μg GSK239512 in combination with repeated once daily doses of 400 mg ketoconazole. The results from Cohort 1 demonstrated an approximately 1.5-fold increase in GSK239512 exposure with a good tolerability profile. This led to the adoption of a 3-session option in Cohort 2, in which 16 subjects received sequential single doses of 20 μg GSK239512 alone, 40 μg GSK239512 alone, and a single dose of 40 μg GSK239512 in combination with repeated once daily doses of 400 mg ketoconazole. The 2-cohort adaptive design proved effective in mitigating any potentially significant DDI risk to healthy subjects. Final results showed a 1.3-fold increase in GSK239512 exposure with ketoconazole, suggesting that in vivo metabolism of GSK239512 by CYP3A is unlikely to be the primary route of GSK239512 elimination.
- Subjects
BLOOD testing; CONFIDENCE intervals; DRUG antagonism; DRUG interactions; GENES; KETOCONAZOLE; RESEARCH funding; DATA analysis software; DESCRIPTIVE statistics
- Publication
Journal of Clinical Pharmacology, 2015, Vol 55, Issue 5, p505
- ISSN
0091-2700
- Publication type
Article
- DOI
10.1002/jcph.441