Meta-Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure

Abstract

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta-analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration-time curve (AUC) or maximum observed plasma concentration (Cmax ) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9-2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and Cmax increased in a dose-proportional manner over the dose range of 0.5-300 mg, and population-predicted AUC and Cmax values for the 5- and 15-mg ertugliflozin tablets administered in the fasted state demonstrated good agreement with the observed data. The largest change in ertugliflozin AUC was in subjects carrying the UGT1A9*3 heterozygous variant, with population-predicted AUC (90% confidence interval) values of 485 ng·h/mL (458 to 510 ng·h/mL) and 1560 ng·h/mL (1480 to 1630 ng·h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng·h/mL (418 to 455 ng·h/mL) and 1410 ng·h/mL (1350 to 1480 ng·h/mL), respectively, in wild-type subjects. Overall, the mean effects of the selected UGT1A9 variants on ertugliflozin AUC were within ±10% of the wild type. UGT1A9 genotype did not have any clinically meaningful effects on ertugliflozin exposure in healthy subjects. No ertugliflozin dose adjustment would be required in patients with the UGT1A9 variants assessed in this study.

Trial registration: ClinicalTrials.gov NCT00989079 NCT01018823 NCT01127308 NCT01114568 NCT01223339 NCT01948986 NCT02115347 NCT02411929.

Keywords: UDP-glucuronosyltransferase 1A9; ertugliflozin; genotype; pharmacogenetics; pharmacokinetics.

Conflict of interest statement

J.‐C.M., V.S., T.T., D.J.F., V.K.D., L.S.W., and K.S. are employees of Pfizer Inc., New York, New York, and may own shares/stock options in Pfizer Inc., New York, New York. Y.L. was an employee of Pfizer Inc., New York, New York, at the time the study was conducted. S.Z. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, and may own stock in Merck & Co., Inc., Kenilworth, New Jersey. R.K. was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, at the time the study was conducted and may own stock in Merck & Co., Inc., Kenilworth, New Jersey.

© 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Observed ertugliflozin dose‐normalized (A) AUC and (B) Cmax values by dose from the dose‐proportionality analysis. Red circles represent dose‐normalized AUCinf or dose‐normalized Cmax following a single dose; black triangles represent dose‐normalized AUCtau at steady state; geometric mean values for each dose group are represented by blue asterisks. AUC, area under the plasma concentration‐time curve; AUCinf, AUC from time zero extrapolated to infinite time; AUCtau, AUC from time zero to time tau, the dosing interval, for which tau is 24 hours; Cmax, maximum observed plasma concentration; SD, single dose; SS, steady state.

Figure 2

Population‐predicted, individual‐predicted, and observed ertugliflozin (A, B) AUC and (C, D) Cmax values by dose from the full model in the dose‐proportionality analysis. Results are shown across the full dose range (A, C) and across the 0.5‐ to 15‐mg dose range (B, D). AUC, area under the plasma concentration‐time curve; Cmax, maximum observed plasma concentration.

Figure 3

Observed ertugliflozin dose‐normalized AUC values by (A) dose and (B) UGT1A9 genotype from the UGT1A9 genotype analysis. (A) Red circles represent dose‐normalized AUCinf following a single dose; black triangles represent dose‐normalized AUCtau at steady state; geometric means for each dose group are represented by blue asterisks. (B) Open circles represent individual subject dose‐normalized AUC values. Box plot provides median and 25%/75% quartiles with whiskers to the last point within 1.5× interquartile range. AUC, area under the plasma concentration‐time curve; AUCinf, AUC from time zero extrapolated to infinite time; AUCtau, AUC from time zero to time tau, the dosing interval, for which tau is 24 hours; het, heterozygous; hom, homozygous; SD, single dose; SS, steady state; WT, wild type.

Figure 4

UGT1A9 polymorphic effects on ertugliflozin AUC from the UGT1A9 genotype analysis. The 90th percentiles of the bootstrap confidence intervals for AUC are provided. Effects are reported relative to the wild‐type subjects in the analysis. A value of 1 represents no change relative to the wild type. AUC, area under the plasma concentration‐time curve.