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

Sangeeta Raje, Ernesto Callegari, Vaishali Sahasrabudhe, Alfin Vaz, Haihong Shi, Eric Fluhler, Eric J Woolf, Klaas Schildknegt, Kyle Matschke, Christine Alvey, Susan Zhou, Dimitris Papadopoulos, Robert Fountaine, Didier Saur, Steven G Terra, Lloyd Stevens, Daniel Gaunt, David L Cutler, Sangeeta Raje, Ernesto Callegari, Vaishali Sahasrabudhe, Alfin Vaz, Haihong Shi, Eric Fluhler, Eric J Woolf, Klaas Schildknegt, Kyle Matschke, Christine Alvey, Susan Zhou, Dimitris Papadopoulos, Robert Fountaine, Didier Saur, Steven G Terra, Lloyd Stevens, Daniel Gaunt, David L Cutler

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 (Fa ) 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-AUCi.v. )*(14 C-Dosei.v. /Dosep.o. )) and Fa ((14 C_Total_Urinep.o. /14 C_Total_Urinei.v. )* (14 C-Dosei.v. /14 C-Dosep.o. )) were estimated. Estimates of F and Fa were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.

© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Study design. Tmax, time to maximum concentration.
Figure 2
Figure 2
Median plasma concentration‐time profiles for oral (unlabeled; 15 mg) and i.v. (14C‐labeled; 100 μg) ertugliflozin.
Figure 3
Figure 3
Individual and geometric mean dose‐normalized area under the plasma concentration‐time curve extrapolated to infinity (AUCinf(dn)) values for unlabeled ertugliflozin and 14C‐ertugliflozin. Circles represent individual values and dots represent geometric means. Box plot provides median and 25%/75% quartiles with whiskers to the last point within 1.5 × interquartile range.

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