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...

ClinicalTrials.gov: NCT02387606; EudraCT number: 2014-005041-41.

Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45μg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15μg commercial presentation. All treatments were generally safe and well-tolerated.

These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.

Adding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631.