Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Abstract

Ertugliflozin, a sodium glucose cotransporter-2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two-period study design with ¹⁴ C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (F_a ) of ertugliflozin. Eight healthy adult men received 100-μg i.v. ¹⁴ C-ertugliflozin (400 nCi) dose 1 h after a 15-mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg ¹⁴ C-ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concentrations were determined using high-performance liquid-chromatography tandem mass spectrometry (HPLC-MS/MS). ¹⁴ C-ertugliflozin plasma concentrations were determined using HPLC-accelerator mass spectrometry (AMS) and ¹⁴ C urine concentrations were determined using AMS. F ((area under the curve (AUC)_p.o. /¹⁴ C-AUC_i.v. )*(¹⁴ C-Dose_i.v. /Dose_p.o. )) and F_a ((¹⁴ C_Total_Urine_p.o. /¹⁴ C_Total_Urine_i.v. )* (¹⁴ C-Dose_i.v. /¹⁴ C-Dose_p.o. )) were estimated. Estimates of F and F_a were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.