The effect of Sonidegib (LDE225) on the pharmacokinetics of bupropion and warfarin in patients with advanced solid tumors.

AIMS We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6). METHODS This was a multi-center, open-label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumors. Cohort 1 patients received a single warfarin 15 mg dose on Day 1 of the run-in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration. Cohort 2 patients received a single bupropion 75 mg dose on Day 1 of run-in period and on C2D22 of sonidegib administration. Sonidegib 800 mg QD oral dosing began on Cycle 1 Day 1 of a 28-day cycle after the run-in period in both cohorts. RESULTS The geometric means ratio (GMR) [90% CIs] for (S)-warfarin with and without sonidegib were: AUCinf 1.15 [1.07, 1.24], and Cmax 0.88 [0.81, 0.97], and (R)-warfarin were: AUCinf 1.10 [0.98, 1.24], and Cmax 0.93 [0.87, 1.0]. The GMR [90% CIs] of bupropion with and without sonidegib were: AUCinf 1.10 [0.99, 1.23], and Cmax 1.16 [0.95, 1.42]. Sonidegib 800 mg had a safety profile that was similar to that of lower dose sonidegib 200 mg and was unaffected by single doses of the probe drugs. CONCLUSIONS Sonidegib dosed orally at 800 mg daily (higher than the FDA approved dose) did not impact the pharmacokinetics or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the pharmacokinetics of bupropion (CYP2B6 probe substrate).