Absolute oral bioavailability and pharmacokinetics of canagliflozin: A microdose study in healthy participants

Absolute oral bioavailability of canagliflozin was assessed by simultaneous oral administration with intravenous [C-14]-canagliflozin microdose infusion in nine healthy men. Pharmacokinetics of canagliflozin, [C-14]-canagliflozin, and total radioactivity, and safety and tolerability were assessed at prespecified timepoints. On day 1, single-dose oral canagliflozin (300 mg) followed 105 minutes later by intravenous [C-14]-canagliflozin (10 mu g, 200 nCi) was administered. After oral administration, the mean (SD) C-max of canagliflozin was 2504 (482) ng/mL at 1.5 hours, AUC(infinity) 17,375 (3555) ng.h/mL, and t(1/2) 11.6 (0.70) hours. After intravenous administration, the mean (SD) C-max of unchanged [C-14]-canagliflozin was 17,605 (6901) ng/mL, AUC(infinity) 27,100 (10,778) ng.h/mL, Vd(ss) 83.5 (29.2) L, Vd(z) 119 (41.6) L, and CL 12.2 (3.79) L/h. Unchanged [C-14]-canagliflozin and metabolites accounted for about 57% and 43% of the plasma total [C-14] radioactivity AUC(infinity), respectively. For total [C-14] radioactivity, the mean (SD) C-max was 15,981 (2721) ng-eq/mL, and AUC(infinity) 53,755 (15,587) ng-eq.h/mL. Renal (34.5% in urine) and biliary (34.1% in feces) excretions were the major elimination pathways for total [C-14] radioactivity. The absolute oral bioavailability of canagliflozin was 65% (90% confidence interval: 55.41; 76.07). Overall, oral canagliflozin 300 mg coadministered with intravenous [C-14]-canagliflozin (10 mu g) was generally well-tolerated in healthy men, with no treatment-emergent adverse events.