Yves Horsmans1, Jocelyn Zhou2, Mateva Liudmila3, George Golor4, Oren Shibolet5, Michelle Quinlan2, Corinne Emotte6, Hildegard Boss6, Henry Castro6,7, Dalila Sellami2, Richard A Preston8,9. 1. Cliniques Saint-Luc, UCL St Luc Bruxelles, Avenue Hippocrate, 10, 1200, Brussels, Belgium. Yves.Horsmans@uclouvain.be. 2. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 3. UMHAT "Sveti Ivan Rilski" EAD, Sofia, Bulgaria. 4. Early Phase Clinical Unit, PAREXEL International GmbH, Berlin, Germany. 5. Tel Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel. 6. Novartis Pharma AG, Basel, Switzerland. 7. Bristol Myers Squibb (BMS), Princeton, NJ, USA. 8. Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA. 9. Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.
Abstract
BACKGROUND AND OBJECTIVE: Sonidegib is a potent, selective and orally bioavailable inhibitor of the Hedgehog signaling pathway, primarily metabolized by the liver. In order to make dose recommendations for patients with hepatic impairment, we have assessed here the pharmacokinetics (PKs) and safety of sonidegib in subjects with varying degrees of hepatic function. METHODS: The primary objective of this phase I, multicenter, open-label study was to evaluate the PKs of a single oral 800 mg dose of sonidegib in subjects with impaired hepatic function compared with healthy subjects. PK parameters (e.g. area under the concentration-time curve from time zero to infinity [AUCinf], area under the concentration-time curve from time zero to the last measurable concentration [AUClast], maximum concentration [C max], apparent clearance [CL/F], and terminal half-life [t ½]) for parent drug and the metabolite were compared with the normal group, as the reference. Metabolite ratio, unbound PK parameters, and the relationship between specific PK parameters and liver function parameters were assessed. RESULTS: In total, 33 subjects entered the study and received sonidegib. Plasma concentrations peaked at approximately 2-3 h in all groups after dosing. Compared with the normal group, AUClast decreased by 35 and 23% and increased by 14% in the mild, severe, and moderate hepatic impairment groups, respectively. The C max values were lower in all groups with respect to the normal group (decreases of 20, 21 and 60% in the mild, moderate and severe hepatic impairment groups, respectively). Protein binding was independent of hepatic function, and similar trends in the PK parameters were observed for unbound sonidegib and the metabolite. Protein binding was similar across all groups. Weak to no correlation between specific PK and hepatic function parameters was found. CONCLUSIONS: Overall, sonidegib exposures were similar or decreased in the hepatic impairment groups compared with the normal group, and sonidegib was generally well-tolerated in all subjects. Dose adjustment is not considered necessary for subjects with mild, moderate, or severe hepatic impairment.
BACKGROUND AND OBJECTIVE: Sonidegib is a potent, selective and orally bioavailable inhibitor of the Hedgehog signaling pathway, primarily metabolized by the liver. In order to make dose recommendations for patients with hepatic impairment, we have assessed here the pharmacokinetics (PKs) and safety of sonidegib in subjects with varying degrees of hepatic function. METHODS: The primary objective of this phase I, multicenter, open-label study was to evaluate the PKs of a single oral 800 mg dose of sonidegib in subjects with impaired hepatic function compared with healthy subjects. PK parameters (e.g. area under the concentration-time curve from time zero to infinity [AUCinf], area under the concentration-time curve from time zero to the last measurable concentration [AUClast], maximum concentration [C max], apparent clearance [CL/F], and terminal half-life [t ½]) for parent drug and the metabolite were compared with the normal group, as the reference. Metabolite ratio, unbound PK parameters, and the relationship between specific PK parameters and liver function parameters were assessed. RESULTS: In total, 33 subjects entered the study and received sonidegib. Plasma concentrations peaked at approximately 2-3 h in all groups after dosing. Compared with the normal group, AUClast decreased by 35 and 23% and increased by 14% in the mild, severe, and moderate hepatic impairment groups, respectively. The C max values were lower in all groups with respect to the normal group (decreases of 20, 21 and 60% in the mild, moderate and severe hepatic impairment groups, respectively). Protein binding was independent of hepatic function, and similar trends in the PK parameters were observed for unbound sonidegib and the metabolite. Protein binding was similar across all groups. Weak to no correlation between specific PK and hepatic function parameters was found. CONCLUSIONS: Overall, sonidegib exposures were similar or decreased in the hepatic impairment groups compared with the normal group, and sonidegib was generally well-tolerated in all subjects. Dose adjustment is not considered necessary for subjects with mild, moderate, or severe hepatic impairment.