ORIGINAL RESEARCH ARTICLE Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment

The Author(s) 2014. This article is published with open access at Springerlink.com Background and Objectives This study examined the effects of moderate renal impairment on the pharmacoki-netics and pharmacodynamics of canagliflozin in Japanese patients with type 2 diabetes mellitus. Methods Japanese patients with stable type 2 diabetes (12 with moderate renal impairment and 12 with normal renal function or mild renal impairment) were eligible. This was an open-label, randomized, two-way crossover, two-sequence, single-dose study performed at a single center in Japan. The subjects were hospitalized for the pharmacodynamic/phar-macokinetic evaluations. Twenty-four patients received a single dose each of canagliflozin 100 and 200 mg before breakfast in a crossover manner with a 14-day washout between doses. The main outcome measures were pharma-cokinetics of canagliflozin and its main metabolites (M5 and M7) in plasma and urine, and change from baseline in 24-h urinary glucose excretion (DUGE24 h). Results There was no significant effect of moderate renal impairment on the maximum canagliflozin concentration. The ratios of least square means (90 % confidence intervals [CIs]) of moderate renal impairment relative to normal renal function or mild renal impairment were 0.982 (0.821–1.173) and 0.989 (0.827–1.182) for the 100 and 200 mg doses, respectively. The canagliflozin area under the plasma con-centration–time curve was greater in those with moderate renal impairment than in those without, after both canagli-flozin doses (ratio of least square means [90 % CI] 1.258 [1.061–1.490] and 1.216 [1.026–1.441]). DUGE24 h increased after administration of both doses, but in patients with moderate renal impairment, the increase was approxi-mately 70 % of that in patients with normal renal function or mild renal impairment. The incidence of adverse events was low and no patient developed hypoglycemia. Conclusion The pharmacokinetics of canagliflozin are affected by renal function, with slight decreases in renal clearance observed. No effect of renal impairment on th