Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

Abstract

Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concentrations (Tmax) occurring at 1 h (fasted) and 2 h (fed) postdose. The terminal phase half-life ranged from 11 to 18 h and steady-state concentrations were achieved by 6 days after initiating once-daily dosing. Ertugliflozin exposure increased in a dose-proportional manner over the tested dose range of 0.5-300 mg. Ertugliflozin is categorized as a Biopharmaceutical Classification System Class I drug with an absolute bioavailability of ~ 100% under fasted conditions. Administration of the ertugliflozin 15 mg commercial tablet with food resulted in no meaningful effect on ertugliflozin area under the plasma concentration-time curve (AUC), but decreased peak concentrations (Cmax) by 29%. The effect on Cmax is not clinically relevant and ertugliflozin can be administered without regard to food. Mild, moderate, and severe renal impairment were associated with a ≤ 70% increase in ertugliflozin exposure relative to subjects with normal renal function, and no dose adjustment in renal impairment patients is needed based on PK results. Consistent with the mechanism of action of SGLT2 inhibitors, 24-h urinary glucose excretion decreased with worsening renal function. In subjects with moderate hepatic impairment, a decrease in AUC (13%) relative to subjects with normal hepatic function was observed and not considered clinically relevant. Concomitant administration of metformin, sitagliptin, glimepiride, or simvastatin with ertugliflozin did not have clinically meaningful effects on the PK of ertugliflozin or the coadministered medications. Coadministration of rifampin decreased ertugliflozin AUC and Cmax by 39% and 15%, respectively, and is not expected to affect efficacy in a clinically meaningful manner. This comprehensive evaluation supports administration to patients with T2DM without regard to prandial status and with no dose adjustments for coadministration with commonly prescribed drugs, or in patients with renal impairment or mild-to-moderate hepatic impairment based on ertugliflozin PK.

Conflict of interest statement

Daryl J. Fediuk, Gianluca Nucci, Vikas Kumar Dawra, Neeta B. Amin, Steven G. Terra, and Vaishali Sahasrabudhe are employees of Pfizer Inc. and may own shares/stock options in Pfizer Inc. Rebecca A. Boyd was an employee of Pfizer Inc. at the time the studies described in this review were conducted. David L. Cutler and Rajesh Krishna were employees of MSD at the time the studies described in this review were conducted and may own stock in Merck & Co., Inc., Kenilworth, NJ, USA.

Figures

Fig. 1

Chemical structure of ertugliflozin, empagliflozin, canagliflozin, and dapagliflozin

Fig. 2

Median plasma ertugliflozin concentration–time curves following a single-dose administration under fasted conditions and b multiple-dose administration under fed conditions [30]. ERTU ertugliflozin

Fig. 3

Dose-normalized aCmax and b AUC∞ following single-dose administration under fasted conditions; and cCmax and d AUCτ at day 14 following multiple-dose administration under fed conditions [30]. Open gray circles identify individual subject data; closed black circles identify arithmetic means. Box plot provides median and 25%/75% quartiles with whiskers extended to the minimum/maximum value. AUC area under the plasma concentration–time curve, AUC∞ AUC from time zero extrapolated to infinite time, AUCτ AUC from time zero to time tau, the dosing interval, where tau = 24 h, Cmax maximum observed plasma concentration, dn dose-normalized, ERTU ertugliflozin

Fig. 4

Cumulative UGE24 values following a single-dose administration under fasted conditions and b multiple-dose administration under fed conditions [30]. Open gray circles identify individual subject data; closed black circles identify arithmetic means. Box plot provides median and 25%/75% quartiles with whiskers extended to the minimum/maximum value. ERTU ertugliflozin, UGE24 urinary glucose excretion over 0–24 h

Fig. 5

Mean ± SD UGE over time intervals for a ertugliflozin 2.5 mg bid/5 mg qd, and b ertugliflozin 7.5 mg bid/15 mg qd. Figure redrawn from Dawra et al. [35] (licensed under CC BY 4.0). bid twice daily, ERTU ertugliflozin, qd once daily, SD standard deviation, UGE urinary glucose excretion