Pharmacokinetics and pharmacodynamics of once- and twice-daily multiple-doses of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants

Aims: Assess the steady-state pharmacokinetics, pharmacodynamics and safety of once-daily (q.d.) versus twice-daily (b.i.d.) dosing with canagliflozin at the same total daily doses of 100 and 300 mg in healthy participants. Methods: 34 participants (17 in each cohort) were enrolled in this single-center, open-label, multiple-dose, 2-cohort, 2-way crossover study. Participants in each cohort received a total daily dose of either 100 or 300 mg canagliflozin for 5 days with q.d. then b.i.d. dosing or vice versa. Pharmacokinetics and pharmacodynamics were assessed on day 5 of each period. Results: The canagliflozin C-max,C-ss of 100 and 300 mg q.d. dosing were higher by 66% and 72% than corresponding morning C-max,C-ss of the 50 mg and 150 mg b.i.d., regimen, respectively. The geometric mean ratios (90% CI) of b.i.d./q.d. for AUC(0-24h,ss) at total doses of 100 and 300 mg were 97.08 (94.08; 99.62) and 99.32 (94.71; 104.16) respectively. Median t(max) and mean t(1/2) were independent of dose and regimen. Mean (SE) 24-h mean renal glucose threshold values for b.i.d. and q.d. regimens were 59.2 (1.03) and 60.2 (1.03) mg/dL for the 100 mg daily doses and 51.0 (1.04) and 52.5 (1.04) mg/dL for the 300 mg daily doses. Mean (SE) values of 24-h urinary glucose excretion for b.i.d. and q.d. regimens were 52.8 (1.94) and 48.6 (1.94) g for the 100 mg daily doses and 58.6 (3.81) and 57.8 (3.81) g for the 300 mg daily doses. Both doses were safe and well tolerated. Conclusion: Pharmacokinetics and pharmacodynamics of canagliflozin administered q.d. relative to b.i.d. at the same 100 and 300 mg total daily doses were comparable. Overall, canagliflozin was well tolerated.