The effect of sonidegib (LDE225) on the pharmacokinetics of bupropion and warfarin in patients with advanced solid tumours

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 multicentre, open-label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. 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 ratios [90% confidence interval] for (S)-warfarin with and without sonidegib were: area under the concentration–time curve from time 0 to infinity (AUC_inf) 1.15 [1.07, 1.24] and maximum plasma concentration (C_max) 0.88 [0.81, 0.97]; and for (R)-warfarin were: AUC_inf 1.10 [0.98, 1.24] and C_max 0.93 [0.87, 1.0]. The geometric means ratios [90% confidence interval] of bupropion with and without sonidegib were: AUC_inf 1.10 [0.99, 1.23] and C_max 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 QD (higher than the Food and Drug Administration-approved dose) did not impact the PK or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the PK of bupropion (CYP2B6 probe substrate).