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

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 (C-max) 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 C-max increased in a dose-proportional manner over the dose range of 0.5-300 mg, and population-predicted AUC and C-max 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 center dot h/mL (458 to 510 ng center dot h/mL) and 1560 ng center dot h/mL (1480 to 1630 ng center dot h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng center dot h/mL (418 to 455 ng center dot h/mL) and 1410 ng center dot h/mL (1350 to 1480 ng center dot 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.

Automated summary

Ertugliflozin is primarily metabolized by UGT1A9, with its exposure increasing in a dose-proportional manner. UGT1A9 genotype has minimal impact on Ertugliflozin exposure, and no dose adjustment is needed for healthy subjects with specific UGT1A9 variants assessed in the study.