Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, and assessment of dose proportionality in healthy participants

Abstract

Canagliflozin, an orally active inhibitor of sodium glucose co-transporter 2, is approved for the treatment of type-2 diabetes mellitus. The effect of food on the pharmacokinetics of 300 mg canagliflozin, and dose proportionality of 50, 100, and 300 mg canagliflozin, were evaluated, in two studies, in healthy participants. Study 1 used a randomized, 2-way crossover design: canagliflozin 300 mg/day was administered under fasted (Period-1) and fed (Period-2) conditions or vice versa. Study 2 was a 3-way crossover: participants were randomized to receive three single-doses of canagliflozin (50, 100, and 300 mg), one in each period. In both studies, treatment periods were separated by washout intervals of 10-14 days, and pharmacokinetics assessed up to 72 hours postdose of each treatment period. No clinically relevant food effects on canagliflozin exposure parameters were observed: 90% confidence intervals (CIs) for the fed/fasted geometric mean ratios of AUC∞ (ratio: 100.51; 90% CI: 89.47-112.93) and Cmax (ratio: 108.09; 90% CI: 103.45-112.95) were entirely within bioequivalence limits (80-125%). Plasma canagliflozin exposures were dose-proportional as the 90% CI of the slope of the regression line for dose-normalized AUC∞ and Cmax fell entirely within the prespecified limits of -0.124 to 0.124. No clinically significant safety issues were noted, and canagliflozin was generally well-tolerated.

Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects

“…[13][14][15] After oral administration in healthy subjects and in patients with T2DM, canagliflozin was rapidly absorbed, with the median T max occurring 1 to 2 hours postdose. 16 In healthy subjects, the mean AUC of canagliflozin increased in a dose-dependent manner across a wide range of doses (25-1600 mg), whereas C max increased in a dose-proportional manner from 50 to 300 mg 16,17 and even up to 1200 mg (unpublished data). In patients with T2DM, the C max and AUC of canagliflozin also increased in a linear manner over the dose range of 50 to 300 mg. 13 Mean terminal t ½ ranged from 10.6 to 13.1 hours with the 100-and 300-mg doses.…”

“…"Asian" was identified as Asian in the case report form, and data from the population pharmacokinetic analysis for Total, White, and Asian participants were used to generate this graphic. 16 Chinese participants (n ¼ 14): each participant received 2 doses (100 and 300 mg), and there were a total of 28 pharmacokinetic values included in this analysis; data were normalized to a 100-mg dose and a body weight of 70 kg.…”

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

“…Coadministration of canagliflozin 300 mg with high-fat meal (300 mg) had no effect on the C max and AUC relative to fasted condition, thus suggesting no significant impact of food on the bioavailability of canagliflozin [21]. However, based on the potential of canagliflozin potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, administration of canagliflozin as monotherapy is recommended before the first meal of the day [21,22].…”

A review of clinical efficacy and safety of canagliflozin 300 mg in the management of patients with type 2 diabetes mellitus

“…[36] Dose-dependent increase in maximum plasma canagliflozin concentration (C max ), area under the plasma concentration-time curve (AUC), and UGE and decrease in RT G were demonstrated in healthy individuals. [484950] The time to achieve C max (t max ) of canagliflozin 300 mg was 1.5 h and elimination half-life (t 1/2 ) was 12.6 h in healthy individuals, which supports OD dosing. [50] In patients with T2DM, the mean C max was achieved 1–2 h after administration and steady-state concentration was reached after 4 days administration of canagliflozin 100–300 mg OD.…”