Background: Ertugliflozin is a highly selective and potent sodium-glucose co-transporter 2 (SGLT2) inhibitor currently in global development for the treatment of type 2 diabetes mellitus (T2DM). It inhibits renal glucose reabsorption resulting in urinary glucose excretion, thereby reducing plasma glucose and glycated hemoglobin in patients with T2DM. Phase 3 studies have also shown that ertugliflozin, 5 mg and 15 mg administered once daily, is associated with reductions in weight and blood pressure.

Aims: A Phase 1, open-label, parallel-cohort, randomized study was conducted to investigate the single- and multiple-dose pharmacokinetics (PK), tolerability, and safety of ertugliflozin 5 mg and 15 mg in healthy subjects from China.
Method: Overall, 16 (8 male and 8 female) Chinese subjects aged 18–45 years were randomized to one of two parallel cohorts. Each subject received a single dose of ertugliflozin 5 mg (n=8; Cohort 1) or 15 mg (n=8; Cohort 2) under fasted conditions on Day 1 and multiple doses of ertugliflozin 5 mg (Cohort 1) or 15 mg once-daily (Cohort 2) under fed conditions on Days 6–11. Single-dose PK was assessed after single-dose administration on Days 1 and 6. Multiple-dose PK was assessed on Day 11 after six once daily doses. Plasma samples were analyzed for ertugliflozin concentrations using a validated, sensitive and specific high-performance liquid chromatography tandem mass spectrometry method with a linear calibration curve range of 0.5–500 ng/mL. Ertugliflozin PK parameters after single and multiple doses were calculated from the plasma concentration–time data using a standard non-compartmental analysis method. Area under the plasma concentration–time curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal half-life (t1/2), and accumulation ratio were summarized descriptively by treatment and study day. Adverse events (AEs), vital signs and laboratory test data were collected for assessment of safety and tolerability.

Results: All 16 subjects completed the study. 
Single-Dose PK: After administration of ertugliflozin 5 mg and 15 mg under fasted conditions, the median Tmax was 1 hour for both doses. Mean t1/2 was approximately 10.4 hours and 9.5 hours for ertugliflozin 5 mg and 15 mg, respectively. The geometric mean AUC from time of dosing extrapolated to infinity (AUCinf) and Cmax values on Day 1 were 599.3 ng•h/mL and 112.9 ng/mL for ertugliflozin 5 mg, respectively; and 1606 ng•h/mL and 360.8 ng/mL for ertugliflozin 15 mg, respectively. 
Multiple-Dose PK: On Day 11, the median Tmax was 4 hours and 2 hours for ertugliflozin 5 mg and 15 mg, respectively. Mean t1/2 was approximately 11.9 hours and 10.6 hours for ertugliflozin 5 mg and 15 mg, respectively. The geometric mean AUC from time 0 to tau (dosing interval) at steady state (AUCtau,ss) and Cmax values were 586.0 ng•h/mL and 78.48 ng/mL for ertugliflozin 5 mg, respectively; and 1542 ng•h/mL and 236.5 ng/mL for ertugliflozin 15 mg, respectively. The accumulation ratio after multiple dose administration was approximately 1.3 and 1.2 for ertugliflozin 5 mg and 15 mg, respectively. Steady state appeared to have been reached by Day 9 (after four once-daily doses) based on similar median trough (pre dose) concentrations on Days 9, 10, 11 and 12. 
There were no deaths, serious AEs or discontinuations. The most commonly reported treatment-emergent AE was glucosuria (n=3 of 8 subjects and n=4 of 8 subjects for ertugliflozin 5 mg and 15 mg, respectively), which is related to the mechanism of action of SGLT2 inhibitors. 

Discussion: The absorption of ertugliflozin was rapid with a median Tmax of 1hour post dose under fasted conditions, and 2–4-hours post dose under fed conditions. The geometric mean AUC and Cmax values showed that exposure of ertugliflozin increased in a dose-proportional manner following single- and multiple-dose administration. Single and multiple oral doses of ertugliflozin were well tolerated in healthy Chinese subjects.

Single and multiple dose pharmacokinetics of ertugliflozin in healthy chinese subjects