Effect of Rifampin on the Pharmacokinetics of Ertugliflozin in Healthy Subjects.

PURPOSE: Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor being developed for the treatment of type 2 diabetes mellitus. The primary enzyme involved in the metabolism of ertugliflozin is uridine diphosphate-glucuronosyltransferase (UGT) 1A9, with minor contributions from UGT2B7 and cytochrome P450 (CYP) isoenzymes 3A4, 3A5, and 2C8. Rifampin induces UGT1A9, UGT2B7, CYP3A4, and CYP3A5. Because concurrent induction of these enzymes could affect ertugliflozin exposure, this study assessed the effect of multiple doses of rifampin on the pharmacokinetic properties of single-dose ertugliflozin.

METHODS: Twelve healthy adult subjects were enrolled in this open-label, 2-period, fixed-sequence study and received ertugliflozin 15 mg on day 1 of period 1, followed by rifampin 600 mg once daily on days 1 to 10 in period 2. On day 8 of period 2, ertugliflozin 15 mg was coadministered with rifampin 600 mg. Plasma samples for ertugliflozin pharmacokinetic analysis were collected during 72 hours after dosing on day 1 of period 1 and day 8 of period 2 and analyzed using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated using noncompartmental analysis of concentration-time data. Natural log transformed AUC0-∞ and Cmax of ertugliflozin were analyzed using a mixed-effects model with treatment as a fixed effect and subject as a random effect.

FINDINGS: After administration of ertugliflozin 15 mg alone or with rifampin, the Tmax was 1 hour. The mean t½ was 12.3 hours for ertugliflozin alone and 9.2 hours with steady-state rifampin. Geometric mean ratios for AUC0-∞ and Cmax were 61.2% (90% CI, 57.2%-65.4%) and 84.6% (90% CI, 74.2%-96.5%), respectively. Ertugliflozin was well tolerated when administered alone or with rifampin.

IMPLICATIONS: Coadministration of ertugliflozin with rifampin decreased ertugliflozin AUC0-∞ and Cmax by 39% and 15%, respectively. The effect of the reduced exposure was evaluated using the ertugliflozin dose-response model. The model predicted that a 5-mg ertugliflozin dose after coadministration with rifampin is expected to maintain clinically meaningful glycemic efficacy. Therefore, no dose adjustment of ertugliflozin is recommended when ertugliflozin is coadministered with a UGT and CYP inducer, such as rifampin. (Clin Ther. 2018;XX:XXX-XXX) © 2018 Elsevier HS Journals, Inc.