Safety, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Luseogliflozin Dosing in Healthy Japanese Males: A Randomized, Single-Blind, Placebo-Controlled Trial

Abstract

IntroductionLuseogliflozin, a sodium glucose cotransporter 2 inhibitor, inhibits reabsorption of glucose in the proximal renal tubule. It was developed for the treatment of type 2 diabetes mellitus.MethodsFor this first human study of luseogliflozin, randomized, single-blind, placebo-controlled, single ascending dose (1–25 mg) and multiple ascending dose (5 or 10 mg/day, 7 days) trials were conducted in healthy male Japanese subjects to investigate safety, pharmacokinetics, and pharmacodynamics.ResultsThere were no serious adverse events, adverse events leading to discontinuation, or episodes of hypoglycemia. After administration of a single oral dose of luseogliflozin, its maximum plasma level (Cmax) and area under the concentration–time curve increased in a dose-dependent manner, and no food effects were observed on pharmacokinetics. The mean time taken to reach Cmax (Tmax) ranged from 0.667 to 2.25 h. The mean plasma half-life of luseogliflozin (T1/2) after multiple dosing for 7 days ranged from 9.14 to 10.7 h, and no detectable accumulation of luseogliflozin was observed. Urinary glucose excretion increased in a dose-dependent manner, ranging from 18.9 to 70.9 g (single-dose study).ConclusionLuseogliflozin was well tolerated and showed favorable pharmacokinetic and pharmacodynamic profiles in healthy male Japanese subjects.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-014-0102-3) contains supplementary material, which is available to authorized users.

Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study

“…In a phase I study of luseogliflozin in healthy individuals 17 and a clinical pharmacology study that assessed the pharmacokinetic and pharmacodynamic profiles of luseogliflozin in patients with T2DM 18 , luseogliflozin dose dependently increased urinary glucose excretion without causing hypoglycemia.…”

Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, placebo-controlled, phase II study

“…The procedure of allocation and procedures implemented to maintain blinding are summarized in Supplementary appendix 1. The doses of luseogliflozin were chosen based on the safety, pharmacokinetic, and pharmacodynamic data of earlier Phase I studies in healthy Japanese males 19 . The study drugs were taken orally, once daily before breakfast.…”

“…However, the effects of luseogliflozin on hyperglycemia and insulin secretion in clinical settings have not been investigated in detail. In one clinical study, single and multiple doses of luseogliflozin dose dependently increased urinary glucose excretion without causing hypoglycemia in healthy Japanese males 19 . Additionally, the administration of luseogliflozin for 7 days significantly increased urinary glucose excretion and decreased plasma glucose levels in Japanese patients with T2DM 20 .…”

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

“…Studies in Japanese patients with T2DM have confirmed that treatment with luseogliflozin increases urinary glucose excretion (UGE) and reduces plasma glucose levels. [7][8][9][10][11][12] In a clinical pharmacology study conducted in Japanese patients with T2DM, reported by Sasaki et al, intensive sampling of UGE (nine sampling intervals a day) was performed and UGE change from pre-dose was analyzed; a significant increase in UGE was observed with once-daily luseogliflozin administration. The UGE was dose-dependent and the relationship of change in daily UGE and area under the curve (AUC) 0-24h of plasma luseogliflozin could be expressed by means of the E max model.…”