Absolute oral bioavailability and pharmacokinetics of canagliflozin: A microdose study in healthy participants. Issue 4 (11th December 2014)

• Record Type: Journal Article
• Authors: Devineni, Damayanthi; Murphy, Joseph; Wang, Shean‐Sheng; Stieltjes, Hans; Rothenberg, Paul; Scheers, Ellen; Mamidi, Rao N.V.S.
• Is Part Of: Clinical pharmacology in drug development. Volume 4:Issue 4(2015:Jul./Aug.)
• Page Start: 295
• Page End: 304
• Publication Date: 2014-12-11
• Subjects: Drugs -- Testing -- Periodicals; Drug development -- Periodicals; Clinical pharmacology -- Periodicals; 615.580724
• DOI: 10.1002/cpdd.162
• Languages: English
• ISSNs: 2160-7648

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="cpdd162-sec-0001" sec-type="section"> <p>Absolute oral bioavailability of canagliflozin was assessed by simultaneous oral administration with intravenous [<sup>14</sup>C]‐canagliflozin microdose infusion in nine healthy men. Pharmacokinetics of canagliflozin, [<sup>14</sup>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 [<sup>14</sup>C]‐canagliflozin (10 µg, 200 nCi) was administered. After oral administration, the mean (SD) C<sub>max</sub> of canagliflozin was 2504 (482) ng/mL at 1.5 hours, AUC<sub>∞</sub> 17, 375 (3555) ng.h/mL, and t<sub>1/2</sub> 11.6 (0.70) hours. After intravenous administration, the mean (SD) C<sub>max</sub> of unchanged [<sup>14</sup>C]‐canagliflozin was 17, 605 (6901) ng/mL, AUC<sub>∞</sub> 27, 100 (10, 778) ng.h/mL, Vd<sub>ss</sub> 83.5 (29.2) L, Vd<sub>z</sub> 119 (41.6) L, and CL 12.2 (3.79) L/h. Unchanged [<sup>14</sup>C]‐canagliflozin and metabolites accounted for about 57% and 43% of the plasma total [<sup>14</sup>C] radioactivity AUC<sub>∞</sub>, respectively. For total [<sup>14</sup>C] radioactivity, the mean (SD) C<sub>max</sub> was 15, 981 (2721) ng‐eq/mL, and AUC<sub>∞</sub> 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 [<sup>14</sup>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 [<sup>14</sup>C]‐canagliflozin (10 µg) was generally well‐tolerated in healthy men, with no treatment‐emergent adverse events.</p> </sec> </abstract>