An adaptive design to investigate the effect of ketoconazole on pharmacokinetics of GSK239512 in healthy male volunteers

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.