Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects

Abstract

Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects. Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t of 5-6 h. Exposure increased dose-proportionally up to 320 mg. Body weight-corrected exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased C by approximately 30% but did not change AUC. Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE), but food intake condition at administration did not affect it. The exposure-response relationship between plasma average concentration of tofogliflozin (C) and UGE fitted E model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia. Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL C corresponding to the dose of between 20 and 40 mg leads to almost maximum effect of tofogliflozin.

Effects of Child-Pugh B Cirrhosis on Pharmacokinetics of Tofogliflozin, a New Sodium-Glucose Co-Transporter (SGLT2) Inhibitor

“…In this study, cumulative UGE values were comparable between the healthy and the moderately hepatically impaired group, and the increase in tofogliflozin exposure in subjects with moderate hepatic impairment did not clearly enhance their cumulative UGE. It has been reported that in healthy subjects, a single oral dose of tofogliflozin ranging from 10 mg to 640 mg increases UGE dose-dependently, but the increase is much less than doseproportional, especially at doses of > 20 mg [8]. The less than 2-fold increase in tofogliflozin exposure in the moderately hepatically impaired group in this study was expected to be insufficient to significantly enhance UGE.…”

“…The characteristics of tofogliflozin's elimination profile from circulation, as demonstrated by the mass balance study [12], raises the possibility that the increased exposure in subjects with moderate hepatic impairment can be attributed to a reduction in the rate of metabolite formation. Because the carboxylate form, the main metabolite of tofogliflozin, has nearly the same t 1/2 as that of tofogliflozin in healthy subjects [8,9,12], elimination of tofogliflozin by metabolism is considered to be greatly dependent on the rate of formation of the carboxylate form. Two possible explanations can account for the longer median t 1/2 of the carboxylate form in subjects with moderate hepatic impairment.…”

“…Its selectivity for human SGLT2 is 2900 times as great as its selectivity for human SGLT1, as estimated by half-maximal inhibitory concentrations [7]. A study in healthy male subjects showed tofogliflozin to have a favorable pharmacokinetic profile: it was absorbed rapidly, with t max at approximately 1 hour; exposure (C max and AUC) increased dose-proportionally up to 320 mg, and food did not affect AUC; urinary excretion of tofogliflozin ranged from 17.1 % to 27.4 % of the dose; and after multiple once-daily dosing for 7 days, no detectable accumulation was observed [8]. A human mass balance study combined with intravenous microdosing demonstrated high oral bioavailability (97.5 %) [9].…”

A 12‐week, randomized, double‐blind, placebo‐controlled, four‐arm dose‐finding phase 2 study evaluating bexagliflozin as monotherapy for adults with type 2 diabetes

“…1 Inhibition of SGLT2 produces glucosuria and reduces plasma glucose concentration in individuals who are hyperglycaemic but has little effect on plasma glucose concentrations in healthy individuals. [2][3][4][5][6] In addition to their antidiabetic actions, SGLT2 inhibitors have been reported to provide cardiovascular and renal benefits in some patient populations. An improvement in the relative risk of a composite endpoint of hospitalization for heart failure or cardiovascular death has been reported for randomized controlled trials studying empagliflozin, 7 canagliflozin 8,9 and dapagliflozin 10 effects in diabetic adults, and studying dapagliflozin effects in a population not preselected for diabetes, 11 for which the treatment effect in the nondiabetic population was equal to that seen in the diabetic population.…”

Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus

“…Tofogliflozin exhibits dose-proportional and time-independent pharmacokinetics (data on file) and achieves readily steady-state plasma exposures due to an apparent terminal plasma half-life of about 6 days. Basic pharmacokinetics (PK) and pharmacodynamics (PD) profiles of tofogliflozin with healthy subjects are reported and tofogliflozin increases UGE as the dose increases [14]. Single PK profile of tofogliflozin with or without representative anti-T2DM drugs was evaluated in drug-drug interaction study and exposure of tofogliflozin was not affected by concomitant drugs and vice versa [15].…”