RT Journal Article
SR Electronic
T1 A physiologically-based pharmacokinetic modeling approach to predict drug-drug interactions of sonidegib (LDE225) with perpetrators of CYP3A in cancer patients
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.116.073585
DO 10.1124/dmd.116.073585
A1 Heidi J Einolf
A1 Jocelyn Zhou
A1 Christina Won
A1 Lai Wang
A1 Sam Rebello
YR 2017
UL http://dmd.aspetjournals.org/content/early/2017/01/25/dmd.116.073585.abstract
AB 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. This data was 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 (AUC0-240h and Cmax, 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 to 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.