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.

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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.

Palatability of the formulation was reported to be good or excellent. Rabeprazole was well tolerated, with no notable differences in safety among the dose groups.

The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10mg/morphine 20mg, 3.00 and 1.63 respectively for oxycodone 15 mg/morphine 30 mg, and 1.12 and 1.25 respectively for oxycodone 20mg/morphine 40 mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40 mg) and of oxycodone at all doses (10, 15, 20mg) was considered to be clinically relevant based on a difference from placebo of ≥ 2.5 μV. For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points <.001 at all doses). Hyperalgesia developed over time vs baseline due to acute exposure to UVB irradiation and to topical/occlusive 1% capsaicin solution. For both compounds, the principal onset of analgesic/antihyperalgesic drug effects was around 0.5 hours with an average peak at about 1 to 2 hours and the effect lasting for more than 3 hours (morphine 20 and 30 mg) or 6 hours (morphine 40 mg and oxycodone all doses). In conclusion, the study demonstrated a solid outcome of a mixed objective/subjective human experimental algesimetric model to approach dose-response relationships and analgesic/antihyperalgesic effects of 2 opioids.