Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations

Abstract

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. Two population pharmacokinetic (PK) analyses were conducted, using data from up to 17 phase 1 to 3 studies, to characterize ertugliflozin PK parameters in select ethnic subgroups: (1) East/Southeast (E/SE) Asian vs non-E/SE Asian subjects; (2) Asian subjects from mainland China vs Asian subjects from the rest of the world and non-Asian subjects. A 2-compartment model with first-order absorption, lag time, and first-order elimination was fitted to the observed data. For the E/SE Asian vs non-E/SE Asian analysis (13 692 PK observations from 2276 subjects), E/SE Asian subjects exhibited a 17% increase in apparent clearance (CL/F) and 148% increase in apparent central volume of distribution (Vc/F) vs non-E/SE Asian subjects. However, individual post hoc CL/F values were similar between groups when body weight differences were considered. For the second analysis (16 018 PK observations from 2620 subjects), compared with non-Asian subjects, CL/F was similar while Vc/F increased by 44% in Asian subjects from mainland China and both CL/F and Vc/F increased in Asian subjects from the rest of the world (8% and 115%, respectively) vs non-Asian subjects. Increases in Vc/F would decrease the ertugliflozin maximum concentration but would not impact area under the concentration-time curve. Therefore, the differences in CL/F (area under the concentration-time curve) and Vc/F were not considered clinically relevant or likely to result in meaningful ethnic differences in the PK of ertugliflozin.

Trial registration: ClinicalTrials.gov NCT00989079 NCT01127308 NCT01054300 NCT01223339 NCT01948986 NCT01096667 NCT01059825 NCT01986855 NCT02033889 NCT02099110 NCT01958671 NCT02630706.

Keywords: diabetes; ertugliflozin; population pharmacokinetics; sodium-glucose cotransporter 2 inhibitor.

Conflict of interest statement

D.J.F., V.S., V.K.D., and K.S. are employees of Pfizer Inc., New York, NY, USA and may own shares/stock options in Pfizer Inc. S.Z. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may own stock in Merck & Co., Inc., Kenilworth, NJ, USA.

© 2021 Merck Sharp & Dohme Corp and Pifzer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Final model individual post hoc apparent clearance (CL/F) for E/SE Asian and non‐E/SE Asian subjects. Boxes provide median and 25th and 75th percentiles, and the lower/upper whiskers extend to 1.5× the interquartile range. Data points beyond the end of the whiskers are outliers. CL/F, individual post hoc apparent clearance; E/SE, East/Southeast.

Figure 2

Final model individual post hoc apparent clearance (CL/F) for non‐Asian subjects, Asian subjects from mainland China, and Asian subjects from the rest of the world. Boxes provide median and 25th and 75th percentiles, and the lower/upper whiskers extend to 1.5× the interquartile range. Data points beyond the end of the whiskers are outliers. CL/F, individual post hoc apparent clearance; ROW, rest of the world.