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 14C 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. 14C‐ertugliflozin (400 nCi) dose 1 h after a 15‐mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg 14C‐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). 14C‐ertugliflozin plasma concentrations were determined using HPLC‐accelerator mass spectrometry (AMS) and 14C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o./14C‐AUCi.v.)*(14C‐Dosei.v./Dosep.o.)) and Fa ((14C_Total_Urinep.o./14C_Total_Urinei.v.)* (14C‐Dosei.v./14C‐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.

Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

“…6 Ertugliflozin AUC inf and C max values following 15-mg dosing in the current study of Chinese subjects are comparable with those in Western subjects (AUC inf : 1113-1636 ng·h/mL; C max : 169-319 ng/mL, in Western subjects) after receiving the same single doses of 15 mg of ertugliflozin. 15,[17][18][19][20][21] A pooled analysis of the current study of Chinese subjects together with 16 other phase 1 studies conducted in healthy subjects showed geometric means of dose normalized AUC inf and C max after single-dose administration in Chinese subjects are 1.20-and 1.34fold of those in non-Asian subjects, respectively (data on file). Similarly, following multiple-dose administration of ertugliflozin under fed conditions in 3 studies, geometric mean of dose normalized AUC tau and C max in Chinese subjects are 1.33-and 1.50-fold of those in non-Asian subjects, respectively.…”

“…19 The terminal elimination half-life (t ½ ) of ertugliflozin ranges from 11 to 17 hours. 5,6,[15][16][17][18][19][20][21][22] The PK of ertugliflozin are similar in healthy subjects and in patients with T2DM. 20 The major clearance pathway of ertugliflozin is metabolism via glucuronidation (86%) with minor contribution from oxidative metabolism (12%).…”

“…[7][8][9][10][11][12][13][14] Ertugliflozin is rapidly absorbed following oral administration, with maximal plasma concentration (C max ) occurring after approximately 1 hour when administered in the fasted state. 6,[15][16][17][18][19] The absolute bioavailability of ertugliflozin is approximately 100% 15 ; its exposure increases in a dose-proportional manner over a dose range of 0.5 to 300 mg 5,6 ; and administration with food does not have a clinically meaningful effect on pharmacokinetics (PK). 19 The terminal elimination half-life (t ½ ) of ertugliflozin ranges from 11 to 17 hours.…”

Bioequivalence of Ertugliflozin/Sitagliptin Fixed‐Dose Combination Tablets and Coadministration of Respective Strengths of Individual Components

“…Absolute bioavailability of ertugliflozin is ∼100% . The terminal‐phase half‐life (t ½ ) is in the range of 11 to 17 hours .…”

“…6 The area under the plasma concentration-time curve (AUC) for ertugliflozin increases in a dose-proportional manner over the dose range of 0.5 to 300 mg. 7 Absolute bioavailability of ertugliflozin is ß100%. 8 The terminal-phase half-life (t ½ ) is in the range of 11 to 17 hours. 7 After oral administration of a radioactive ertugliflozin dose, excretion of radioactivity in urine and feces accounted for 50.2% and 40.9% of the dose, respectively.…”