Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Sodium Glucose Co‐Transporter 2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus

Abstract

This study characterized single-and multiple-dose pharmacokinetics of canagliflozin and its O-glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RT G ], urinary glucose excretion ], and 24-hour mean plasma glucose ]) of canagliflozin in subjects with type 2 diabetes. Thirty-six randomized subjects received canagliflozin 50, 100, or 300 mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration-time curve and maximum observed plasma concentration (C max ) for canagliflozin and its metabolites increased dose-dependently. Half-life and time at which C max was observed were dose-independent. Systemic molar M5 exposure was half that of canagliflozin; M7 exposure was similar to canagliflozin. Steady-state plasma canagliflozin concentrations were reached by Day 4 in all active treatment groups. Pharmacodynamic effects were dose-and exposure-dependent. All canagliflozin doses decreased RT G , increased UGE 0-24h , and reduced MPG 0-24h versus placebo on Days 1 and 7. On Day 7, placebo-subtracted least-squares mean decreases in MPG 0-24h ranged from 42-57 mg/dL with canagliflozin treatment. Adverse events (AEs) were balanced between treatments; no treatment-related serious AEs, AE-related discontinuations, or clinically meaningful adverse changes in routine safety evaluations occurred. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in subjects with type 2 diabetes supports a once-daily dosing regimen. Keywordscanagliflozin, sodium glucose co-transporter 2 inhibitor, type 2 diabetes mellitus, pharmacokinetics, pharmacodynamicsIn humans, glucose is freely filtered through the renal glomerulus and then reabsorbed in the proximal tubules. The renal threshold for glucose (RT G ) is the plasma glucose (PG) concentration at which tubular reabsorption of glucose begins to saturate; glucose is excreted into the urine in direct proportion to the glucose concentration above this threshold. The sodium glucose co-transporter 2 (SGLT2) is responsible for the majority of filtered glucose reabsorption from the lumen. 1,2 Patients with diabetes have been shown to have elevated renal glucose reabsorption, which may contribute to persistent elevated PG concentrations. 3,4 Canagliflozin, an orally active inhibitor of SGLT2, is currently in development for the treatment of patients with type 2 diabetes mellitus. 5,6 By inhibiting SGLT2, canagliflozin inhibits glucose reabsorption in renal proximal tubular cells, thereby reducing the RT G . 7,8 In preclinical models of diabetes, canagliflozin reduces RT G , increases urinary glucose excretion (UGE), decreases PG, reduces weight gain, and improves b-cell function. 9 In a multiple-dose clinical study in healthy subjects, once-daily, orally administered canagliflozin decreased the 24-hour mean RT G and increased UGE in a dosedependent manner while 24-hour mean PG (MPG 0-24h ) levels were not affected by canagliflozin treatment. 6 Maximal lowering of the 24-hour mean RT G to approximately 60 mg/dL and in...

Bioequivalence of Canagliflozin/Metformin Immediate Release Fixed- Dose Combination Tablets Compared with Concomitant Administration of Single Components of Canagliflozin and Metformin in Healthy Fed Participants

“…This indicates that the FDC is bioequivalent to coadministration with respect to either canagliflozin or metformin pharmacokinetics with no effects on its rate and extent of absorption as well as its elimination attributed to the formulation performance factors of the FDC tablet. Canagliflozin pharmacokinetics from administration of FDC and co-administration of individual tablets were consistent with single-and multi-dose pharmacokinetics of canagliflozin alone (50, 100, and 300 mg) in healthy participants and in adults with T2DM that showed C max and AUC increased in a dose-dependent manner across all 3 doses [37,38]. The single-dose pharmacokinetics of metformin observed in the bioequivalent studies are consistent with previously reported studies of metformin alone in healthy participants [39].…”

Functional expression of sodium-glucose transporters in cancer

“…Subcutaneous ASPC-1 tumors produced in the upper thigh or lower flank of NSG mice were monitored for up to 4 wk during treatment with 30 mg/kg canagliflozin or dapagliflozin. The protocol for SGLT2 inhibitors was the one developed for inhibiting renal SGLT2 in mice and patients with diabetes (27)(28)(29)(30). As a positive control, we included treatment with the anticancer drug gemcitabine.…”

Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS)

“…Canagliflozin lowers plasma glucose by promoting urinary glucose excretion, which results in a mild osmotic diuresis that may be associated with a reduction in intravascular volume 6, 7, 8, 9. While the insulin‐independent mechanism of canagliflozin leads to a low inherent risk of hypoglycaemia, the mild osmotic diuresis it causes may be associated with an increased risk of volume–depletion events, including dehydration.…”