title: An adaptive design to investigate the effect of ketoconazole on pharmacokinetics of GSK239512 in healthy male volunteers.
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.
authors.affiliation: GSKR R&D, Shanghai, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Jan
authors.initials: J
authors.lastname: Hilpert
authors.forename: Kai
authors.initials: K
authors.lastname: Wu
authors.forename: Benjamin
authors.initials: B
authors.lastname: van Hecke
authors.forename: Gary
authors.initials: G
authors.lastname: Collins
authors.forename: Aarti
authors.initials: A
authors.lastname: Patel
authors.forename: Rajat
authors.initials: R
authors.lastname: Mohindra
authors.forename: Matt J B
authors.initials: MJ
authors.lastname: Davies
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Xu
authors.forename: Paul
authors.initials: P
authors.lastname: Thompson
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006207:Half-Life; D064368:Healthy Volunteers; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012107:Research Design; D055815:Young Adult
chemical_list: D001552:Benzazepines; D065692:Cytochrome P-450 CYP3A Inhibitors; C584220:GSK239512; D006633:Histamine Antagonists; D007654:Ketoconazole
keywords: GSK239512; H3 receptor antagonist; drug-drug interaction; ketoconazole; pharmacokinetics