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SummaryOf the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10–30 minutes of administration and sustained for at least 24 hours.Institution where the work was performed: Duke University Clinical Research Unit, Duke University Medical Center, Durham, NC USA

Summary.Technosphere/Insulin (TI) is a formulation of regular human insulin and Technosphere, a new drug delivery system for pulmonary administration. The formulation is designed for efficient transport of insulin across the intact respiratory epithelium into the systemic circulation. We have investigated the pharmacodynamic and pharmacokinetic properties of Technosphere/Insulin in five healthy, non-smoking volunteers. In an open, randomized, three-way crossover study, subjects received 5 IU regular human insulin (HI) intravenously, 10 IU HI subcutaneously; and 100 IU TI via inhalation using a small commercially available asthma inhaler. The time action profiles of all three insulin formulations were assessed by the euglycemic glucose clamp technique on three different study days. Glucose infusion rates were monitored from 2 h before until 6 h after insulin administration. Other study measures were serum insulin, serum C-peptide concentrations, and safety parameters. The inhalation of TI was well tolerated. The time to peak action was significantly shorter with both i.v. injection and inhalation, as compared to s.c. (14 +/- 6 min and 39 +/- 36 min vs. 163 +/- 25 min; p < 0.0002 and p < 0.007 (mean +/- SD)). The metabolic effect during the first 3 h after insulin administration was higher with inhaled TI than with HI s.c. (AUC0-180 for glucose infusion rate: 1.94 +/- 0.77 mg/kg * min vs. 1.15 +/- 0.50 mg/kg * min; p < 0.04). Relative and absolute bioavailability for the first 3 h were 26 +/- 12% and 15 +/- 5% respectively (6 h: 16 +/- 8 and 16 +/- 6%). We conclude that inhalation of TI leads to a rapid onset of metabolic action resembling the effect observed with i.v. administration of regular HI. Despite the use of a common asthma inhaler, bioavailability over the three hour prandial period was substantially greater than with other reported pulmonary systems. Therefore, inhalation of Technosphere/Insulin may become a suitable and attractive alternative for prandial insulin delivery, especially for patients with type 2 diabetes mellitus.

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Aims/hypothesisThis study evaluates the pharmacodynamic and pharmacokinetic properties of the novel ultra-fast insulin product VIAject, a formulation of human soluble insulin and generally recognised as safe ingredients designed to increase the rate of absorption.MethodsWe performed five euglycaemic glucose clamps (Biostator; target blood glucose 5 mmol/l) in ten healthy volunteers. Using a crossover design with a fixed treatment order, 12 IU human soluble insulin, 12 U insulin lispro and 12 IU ultra-fast insulin were injected s.c. in the abdominal region on three study days. On the other two study days, 6 and 3 IU ultra-fast insulin were injected.ResultsSubcutaneous injection of 12 IU ultra-fast insulin resulted in a time–action profile characterised by an even more rapid onset of action and maximal metabolic activity than insulin lispro: time to early half-maximal activity was 33 ± 17 min (mean ± SD) vs insulin lispro 51 ± 13 min vs human soluble insulin 66 ± 15 min (p < 0.05 ultra-fast insulin