This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 lg/mL and 6.5 to 55409.6 h·lg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested. Key words: ASKP1240, anti-CD40, pharmacodynamics, pharmacokinetics, randomizedAbbreviations: AEs, adverse events; AUC inf , area under the concentration-time curve from time zero extrapolated to the infinite time; C max , maximal antibody serum concentration; INR, international normalized ratio; LLOQ, lower limit of quantification; MABEL, minimal anticipated biological effect level; MedDRA, Medical Dictionary for Regulatory Activities; MFI, mean fluorescent intensity; PD, pharmacodynamic; PDAS, pharmacodynamic analysis set; PK, pharmacokinetic; PKAS, pharmacokinetic analysis set; SAF, safety analysis set; SD, standard deviation; t 1/2 , terminal half-life; t max , time to C max ; ULN, upper limit of normal.

Ipragliflozin did not affect the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa, suggesting that no dose-adjustments are likely to be required when ipragliflozin is given in combination with other glucose-lowering drugs in patients with type 2 diabetes mellitus.

Conclusion:While policies focused on uDCD may increase overall DD rates, increases in DD from policies that focus on cDCD come at the expense of DBD. We conclude that cDCD negatively impacts the number of donations from brain dead donors and may lead to an overall reduction in the number of transplants performed due to reduced organ retrieval rates. 2546A Phase 1b, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Single-Dose, Pharmacokinetic, Pharmacodynamic, Safety and Tolerability Study of ASKP1240 in de novo Kidney Transplantation