title: Absolute oral bioavailability and pharmacokinetics of canagliflozin: A microdose study in healthy participants.
abstract: Absolute oral bioavailability of canagliflozin was assessed by simultaneous oral administration with intravenous [(14) C]-canagliflozin microdose infusion in nine healthy men. Pharmacokinetics of canagliflozin, [(14) C]-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 [(14) C]-canagliflozin (10 µg, 200 nCi) was administered. After oral administration, the mean (SD) Cmax of canagliflozin was 2504 (482) ng/mL at 1.5 hours, AUC∞ 17,375 (3555) ng.h/mL, and t1/2 11.6 (0.70) hours. After intravenous administration, the mean (SD) Cmax of unchanged [(14) C]-canagliflozin was 17,605 (6901) ng/mL, AUC∞ 27,100 (10,778) ng.h/mL, Vdss 83.5 (29.2) L, Vdz 119 (41.6) L, and CL 12.2 (3.79) L/h. Unchanged [(14) C]-canagliflozin and metabolites accounted for about 57% and 43% of the plasma total [(14) C] radioactivity AUC∞ , respectively. For total [(14) C] radioactivity, the mean (SD) Cmax was 15,981 (2721) ng-eq/mL, and AUC∞ 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 [(14) C] radioactivity. The absolute oral bioavailability of canagliflozin was 65% (90% confidence interval: 55.41; 76.07). Overall, oral canagliflozin 300 mg coadministered with intravenous [(14) C]-canagliflozin (10 µg) was generally well-tolerated in healthy men, with no treatment-emergent adverse events.
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Murphy
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Shean-Sheng
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Stieltjes
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Rothenberg
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Scheers
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D000068896:Canagliflozin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D064368:Healthy Volunteers; D065669:Hepatobiliary Elimination; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D000068896:Canagliflozin
keywords: AMS; absolute bioavailability; canagliflozin; microtracer; pharmacokinetics