An adaptive design to investigate the effect of ketoconazole on pharmacokinetics of GSK239512 in healthy male volunteers
| Autor: | Rajat Mohindra, Jianfeng Xu, Kai Wu, Yanmei Xu, Paul D. Thompson, Benjamin van Hecke, Matt J. B. Davies, Aarti Patel, Jan Hilpert, Gary Collins |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Adolescent Metabolic Clearance Rate CYP3A Histamine Antagonists Pharmacology Young Adult chemistry.chemical_compound Pharmacokinetics Humans Medicine Drug Interactions Pharmacology (medical) Dose-Response Relationship Drug business.industry Benzazepines Middle Aged Stepwise regression Healthy Volunteers Ketoconazole chemistry Tolerability Research Design Area Under Curve Adaptive design Cohort Cytochrome P-450 CYP3A Inhibitors business H3 receptor antagonist Half-Life medicine.drug |
| Zdroj: | The Journal of Clinical Pharmacology. 55:505-511 |
| ISSN: | 0091-2700 |
| DOI: | 10.1002/jcph.441 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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