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

Darcy B. Pooler, Dylan B. Ness, John Sarantopoulos, Nicholas Squittieri, Shoba Ravichandran, Carolyn D. Britten, Ravi K. Amaravadi, Ulka Vaishampayan, Patricia LoRusso, Geoffrey I. Shapiro, Anthony J. Olszanski, Raymond Perez, Martin Gutierrez, Mark Allen O’Rourke, Vincent Chung, James J. Lee, Lionel D. Lewis

Research output: Contribution to journalArticlepeer-review

Abstract

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 (AUCinf) 1.15 [1.07, 1.24] and maximum plasma concentration (Cmax) 0.88 [0.81, 0.97]; and for (R)-warfarin were: AUCinf 1.10 [0.98, 1.24] and Cmax 0.93 [0.87, 1.0]. The geometric means ratios [90% confidence interval] 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 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).

Original languageEnglish (US)
JournalBritish Journal of Clinical Pharmacology
DOIs
StateAccepted/In press - 2020

Keywords

  • CYP450 probes
  • bupropion
  • sonidegib
  • warfarin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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