Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Abstract

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, prevents renal glucose reabsorption resulting in urinary glucose excretion. This open-label, parallel cohort, randomized study conducted in healthy Chinese adults residing in China assessed the pharmacokinetics, tolerability, and safety of 5 mg and 15 mg of ertugliflozin following single (fasted condition) and multiple-dose (fed condition) administration. Sixteen subjects were randomized and completed the study. Ertugliflozin absorption was rapid, with maximum plasma concentrations observed 1 hour after dosing under fasted conditions and 2 to 4 hours after dosing under fed conditions. Following single-and multiple-dose administration, ertugliflozin exhibited dose-proportional exposures with an apparent mean terminal halflife of approximately 9.5 to 11.9 hours. Steady state was reached after 4 once-daily doses. The accumulation ratio based on the area under the plasma concentration-time curve after multiple-dose administration was approximately 1.3 and 1.2 for ertugliflozin 5 mg and 15 mg, respectively. Ertugliflozin was generally well tolerated following administration of single and multiple oral doses of 5 mg and 15 mg in healthy Chinese subjects. Pharmacokinetic comparison with non-Asian subjects indicated that there are no clinically meaningful racial differences and no dose modification of ertugliflozin is required based on race or body weight.

Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Healthy Japanese and Western Subjects

“…The PK and PD results in this study are consistent with previous phase 1 studies of ertugliflozin conducted in Western subjects 12 . The results of the current PK analysis in Japanese subjects are also similar to those observed in a study evaluating the PK, safety, and tolerability of ertugliflozin 5 and 15 mg in healthy Chinese adults 20 . Additionally, in the study of Chinese subjects, the R ac was ≈ 1.3 and 1.2 for ertugliflozin 5 and 15 mg, respectively, which is similar to the R ac of 1.2 to 1.4 observed in single‐ and multiple‐dose studies of ertugliflozin conducted in healthy Western subjects 12 .…”

“… 12 The results of the current PK analysis in Japanese subjects are also similar to those observed in a study evaluating the PK, safety, and tolerability of ertugliflozin 5 and 15 mg in healthy Chinese adults. 20 Additionally, in the study of Chinese subjects, the R ac was ≈ 1.3 and 1.2 for ertugliflozin 5 and 15 mg, respectively, which is similar to the R ac of 1.2 to 1.4 observed in single‐ and multiple‐dose studies of ertugliflozin conducted in healthy Western subjects. 12 Findings from a population PK analysis of ertugliflozin have also indicated that race does not have a clinically relevant effect on the PK of ertugliflozin.…”

Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations

“…29 The findings of the 2 separate popPK analyses presented here support both the previously published popPK analysis 22 and phase 1 studies that suggested no clinically meaningful ethnic differences in ertugliflozin PK, and no dose modification of ertugliflozin is required on the basis of race/ethnicity. 20,21 The popPK findings reported here for E/SE Asian subjects vs non-E/SE Asian subjects and for Asian subjects from mainland China vs Asian subjects from the rest of the world and non-Asian subjects are also supported by the results from phase 3 clinical studies. A post hoc analysis of 3 phase 3 clinical studies demonstrated that treatment with ertugliflozin was associated with clinically meaningful reductions in glycated hemoglobin, fasting plasma glucose, body weight, and systolic blood pressure, and was generally well tolerated in patients with T2DM from E/SE Asian countries.…”

“…In a phase 1 study conducted in healthy Chinese subjects, exposure (C max , area under the concentration‐time curve [AUC] from time 0 extrapolated to infinite time, and AUC for a dosing interval at steady state [AUC τ,ss ]) of ertugliflozin increased in a dose‐proportional manner following single‐ and multiple‐dose administration. 20 The apparent terminal elimination half‐life of ertugliflozin ranged from ≈9.5 to 11.9 hours, and the accumulation ratio (based on the AUC) of ertugliflozin exposure after multiple‐dose administration was ≈1.3 and 1.2 for ertugliflozin 5 and 15 mg, respectively. Comparison of observed PK parameters with non‐Asian subjects indicated that there were no clinically meaningful ethnic differences, and no dose modification of ertugliflozin is required on the basis of ethnicity or body weight.…”

Efficacy and safety of ertugliflozin across racial groups in patients with type 2 diabetes mellitus

“…Genetic polymorphisms in the enzymes that metabolize ertugliflozin do not have a clinically meaningful impact on the pharmacokinetics of ertugliflozin 24 . No clinically meaningful racial differences were observed in the pharmacokinetics and pharmacodynamics of ertugliflozin in clinical pharmacology studies carried out in healthy subjects 25,26 . On the basis of these studies, no racial differences in the clinical efficacy and safety of ertugliflozin were expected in the phase III studies of patients with T2DM.…”