Damayanthi Devineni1, David Polidori2, Christopher Curtin3, Hans Stieltjes4, Hong Tian3, Ewa Wajs4. 1. Janssen Research & Development, LLC, Raritan, New Jersey. Electronic address: ddevinen@its.jnj.com. 2. Janssen Research & Development, LLC, San Diego, California. 3. Janssen Research & Development, LLC, Raritan, New Jersey. 4. Janssen Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Abstract
PURPOSE:Canagliflozin, an orally active selective inhibitor of sodium glucose cotransporter 2, has been approved in several countries for the treatment of type 2 diabetes mellitus. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose canagliflozin 200 or 300 mg in healthy Indian participants. METHODS: In this Phase 1, single-center, open-label, 2-period crossover study, healthy adult participants were randomly assigned to receive a single dose of canagliflozin 200 mg in period 1, followed by canagliflozin 300 mg in period 2, or vice versa. The 2 periods were separated by a washout interval of 14 days. The PK and PD properties and tolerability of canagliflozin were assessed at prespecified time points. FINDINGS:Of 15 randomized participants, 14 completed the study. After the administration of single doses of 200 and 300 mg, the mean (SD) Cmax values were 1792 (430) ng/mL and 2789 (941) ng/mL, respectively; AUC0-∞, values were 18,706 (3818) ng·h/mL and 28,207 (5901) ng·h/mL, respectively. The Tmax and t½ of canagliflozin were independent of dose (Tmax, 1.5 hours at both doses; t½, 13.0 and 12.6 hours with 200 and 300 mg). Over the first 4 hours, mean (SD) renal threshold for glucose (RTG) values were 60.8 (8.90) and 61.2 (7.04) mg/dL with the 200- and 300-mg doses, respectively. No effect on plasma glucose concentrations over 0 to 4 hours relative to baseline was observed with either dose. The only treatment-emergent adverse event (TEAE) reported in >1 participant was dizziness (2 participants with the 200-mg dose). None of the participants in the 300-mg group reported any TEAEs. No deaths, discontinuations due to TEAEs, or hypoglycemic episodes were reported. IMPLICATIONS: The mean plasma exposure (Cmax and AUC) to canagliflozin increased in a dose-dependent manner after the administration of single-dose oral canagliflozin 200 and 300 mg in these healthy Indian participants. The Tmax and t½ of canagliflozin appeared to be independent of dose. Overall, PK characteristics were consistent with previous findings in other ethnic populations. The reductions in RTG with canagliflozin were similar to those reported in Western participants, whereas the amount of urinary glucose excretion was somewhat less than those previously observed in studies in Western participants. Canagliflozin was generally well tolerated in these healthy Indian participants. ClinicalTrials.gov identifier: NCT01748526.
RCT Entities:
PURPOSE:Canagliflozin, an orally active selective inhibitor of sodium glucose cotransporter 2, has been approved in several countries for the treatment of type 2 diabetes mellitus. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose canagliflozin 200 or 300 mg in healthy Indian participants. METHODS: In this Phase 1, single-center, open-label, 2-period crossover study, healthy adult participants were randomly assigned to receive a single dose of canagliflozin 200 mg in period 1, followed by canagliflozin 300 mg in period 2, or vice versa. The 2 periods were separated by a washout interval of 14 days. The PK and PD properties and tolerability of canagliflozin were assessed at prespecified time points. FINDINGS: Of 15 randomized participants, 14 completed the study. After the administration of single doses of 200 and 300 mg, the mean (SD) Cmax values were 1792 (430) ng/mL and 2789 (941) ng/mL, respectively; AUC0-∞, values were 18,706 (3818) ng·h/mL and 28,207 (5901) ng·h/mL, respectively. The Tmax and t½ of canagliflozin were independent of dose (Tmax, 1.5 hours at both doses; t½, 13.0 and 12.6 hours with 200 and 300 mg). Over the first 4 hours, mean (SD) renal threshold for glucose (RTG) values were 60.8 (8.90) and 61.2 (7.04) mg/dL with the 200- and 300-mg doses, respectively. No effect on plasma glucose concentrations over 0 to 4 hours relative to baseline was observed with either dose. The only treatment-emergent adverse event (TEAE) reported in >1 participant was dizziness (2 participants with the 200-mg dose). None of the participants in the 300-mg group reported any TEAEs. No deaths, discontinuations due to TEAEs, or hypoglycemic episodes were reported. IMPLICATIONS: The mean plasma exposure (Cmax and AUC) to canagliflozin increased in a dose-dependent manner after the administration of single-dose oral canagliflozin 200 and 300 mg in these healthy Indian participants. The Tmax and t½ of canagliflozin appeared to be independent of dose. Overall, PK characteristics were consistent with previous findings in other ethnic populations. The reductions in RTG with canagliflozin were similar to those reported in Western participants, whereas the amount of urinary glucose excretion was somewhat less than those previously observed in studies in Western participants. Canagliflozin was generally well tolerated in these healthy Indian participants. ClinicalTrials.gov identifier: NCT01748526.