title: A Physiologically-Based Pharmacokinetic Modeling Approach To Predict Drug-Drug Interactions of Sonidegib (LDE225) with Perpetrators of CYP3A in Cancer Patients.
abstract: Sonidegib (Odomzo) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro. The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. These data were used to verify a physiologically-based pharmacokinetic (PBPK) model developed to 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady state and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients. Treatment of healthy subjects with KTZ resulted in an increased sonidegib exposure of 2.25- and 1.49-fold (area under the curve0-240hand maximal concentration respectively), and RIF decreased exposure by 72% and 54%, respectively. The model simulated the single- and/or multiple-dose PK of sonidegib (healthy subjects and patients) within ∼50% of observed values. The effect of KTZ and RIF on sonidegib in healthy subjects was also simulated well, and the predicted DDI in patients was slightly less and independent of sonidegib dose. At steady state, sonidegib was predicted to have a higher DDI magnitude with strong or moderate CYP3A perpetrators compared with a single dose. Different dosing regimens of sondigeb with the perpetrators were also simulated and provided guidance to the current dosing recommendations incorporated in the product label.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (H.J.E., L.W., S.R.) and Oncology Clinical Pharmacology (J.Z., C.W.), Novartis, East Hanover, New Jersey 07936 heidi.einolf@novartis.com.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Einolf
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (H.J.E., L.W., S.R.) and Oncology Clinical Pharmacology (J.Z., C.W.), Novartis, East Hanover, New Jersey 07936.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (H.J.E., L.W., S.R.) and Oncology Clinical Pharmacology (J.Z., C.W.), Novartis, East Hanover, New Jersey 07936.
authors.forename: Christina
authors.initials: C
authors.lastname: Won
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (H.J.E., L.W., S.R.) and Oncology Clinical Pharmacology (J.Z., C.W.), Novartis, East Hanover, New Jersey 07936.
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (H.J.E., L.W., S.R.) and Oncology Clinical Pharmacology (J.Z., C.W.), Novartis, East Hanover, New Jersey 07936.
authors.forename: Sam
authors.initials: S
authors.lastname: Rebello
mesh_terms: D000328:Adult; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors; D013997:Time Factors; D055815:Young Adult
chemical_list: D001713:Biphenyl Compounds; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D011725:Pyridines; C491023:SMO protein, human; D000072086:Smoothened Receptor; C561435:sonidegib; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; D012293:Rifampin