Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Healthy Japanese and Western Subjects

Abstract

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. This randomized, double-blind (sponsor-open) study in healthy Japanese subjects and open-label study in Western subjects assessed ertugliflozin pharmacokinetics and pharmacodynamics. Cohort A received 3 ascending single doses of ertugliflozin (1, 5, and 25 mg; n = 6 Japanese, n = 6 Western) or placebo (n = 3 Japanese) under fasted conditions. Cohort B received multiple once-daily doses of ertugliflozin 25 mg (n = 6 Japanese) or placebo (n = 3 Japanese) for 7 days under fed conditions. For Japanese subjects in Cohort A, maximum plasma concentrations (Cmax ) were observed 1 to 1.5 hours after dosing, and apparent mean terminal half-life was 12.4 to 13.6 hours. The ratios of the geometric means (Japanese/Western) for ertugliflozin 1-, 5-, and 25-mg single doses were 95.94%, 99.66%, and 90.32%, respectively, for area under the plasma concentration-time curve and 107.59%, 97.47%, and 80.04%, respectively, for Cmax . Area under the plasma concentration-time curve and Cmax increased in a dose-proportional manner. For Cohort B, Cmax was observed 2.5 hours after dosing (days 1 and 7), and steady state was reached by day 4. The 24-hour urinary glucose excretion was dose dependent. Ertugliflozin was generally well tolerated. There were no meaningful differences in exposure, urinary glucose excretion, and safety between Japanese and Western subjects.

Trial registration: ClinicalTrials.gov NCT01223339.

Keywords: Japanese; PD; PK; SGLT2 inhibitor; ertugliflozin; type 2 diabetes.

Conflict of interest statement

Y.L. and Y.Y. are employees of Pfizer Research and Development, Japan. G.N. is an employee of Pfizer Inc., Cambridge, Massachusetts. D.J.F. and V.S. are employees of Pfizer Inc., Groton, Connecticut. All authors may own shares/stock options in Pfizer Inc.

© 2021 Pfizer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Mean (standard deviation) plasma ertugliflozin concentration‐time profile in Cohort A in (A) linear (principal plot) with the 0‐ to 12‐hour interval on an expanded time scale (inset plot) and (B) semilogarithmic scales. Summary statistics were calculated by setting concentration values below the lower limit of quantification (0.500 ng/mL) to 0.

Figure 2

Individual, geometric, and arithmetic mean plasma ertugliflozin dose‐normalized (A) Cmax and (B) AUCinf values by dose and population in Cohort A. Open circles and triangles identify individual subject data; closed circles and triangles identify geometric means. Offset crosses identify arithmetic mean (with standard deviation). Box plots provide medians, and 25% and 75% quartiles with whiskers extended to the minimum/maximum values. AUClast, AUC from time 0 to the time of last measurable concentration; Cmax, maximum observed plasma concentration; dn, dose‐normalized.

Figure 3

Mean (standard deviation) plasma ertugliflozin concentration‐time profile in Cohort B in (A) linear (principal plot) with the 0‐ to 12‐hour interval on an expanded time scale (inset plot) and (B) semilogarithmic scales. Summary statistics were calculated by setting concentration values below the lower limit of quantification (0.500 ng/mL) to 0.

Figure 4

Individual and arithmetic mean UGE24 by (A) treatment (ertugliflozin 1, 5, and 25 mg or placebo) and population (healthy Japanese and Western subjects) in Cohort A and by (B) treatment (ertugliflozin 25 mg or placebo) and dosing day (day 1 and 7) in healthy Japanese subjects in Cohort B. Open circles and triangles identify individual subject data; closed circles and triangles identify arithmetic means. Box plots provide medians, and 25% and 75% quartiles with whiskers extended to the minimum/maximum values. UGE24, culmulative urinary glucose excretion over 24 hours.

Figure 5

A total of 24‐hour inhibition of glucose reabsorption by (A) treatment (ertugliflozin 1, 5, and 25 mg or placebo) and population (healthy Japanese and Western subjects) in Cohort A and by (B) treatment (ertugliflozin 25 mg or placebo) and dosing day (days 1 and 7) in healthy Japanese subjects in Cohort B. Open circles and triangles identify individual subject data; closed circles and triangles identify arithmetic means. Box plots provide medians, and 25% and 75% quartiles with whiskers extended to the minimum/maximum values. A total of 24‐hour inhibition (%) of glucose reabsorption was calculated using the equation UGE24/(estimated glomerular filtration rate [mL/min] × fasting glucose concentration [mg•h/dL]) × 0.0144.