HMR1766 is a new nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC) in development for the treatment of cardiovascular diseases and chronic heart failure. A significant fraction of patients to be treated with HMR1766 is expected to be maintained on warfarin. Because HMR1766 is an inhibitor and warfarin a substrate of CYP2C9, the authors studied whether warfarin pharmacokinetics and pharmacodynamics are influenced by HMR1766. Eighteen healthy males were to receive a single oral dose of 20 mg warfarin each under steady-state conditions of HMR1766 or placebo. Plasma concentrations of HMR1766, (R)- and (S)-warfarin, and its 7-hydroxy-metabolites were determined using high-performance liquid chromatography and prothrombin time, and the international standardized ratio was determined by the nephelometric method. (S)-Warfarin AUC(inf) and t(1/2) were 106,471 h x microg/L and 82.92 hours versus 33,148 h x microg/L under HMR1766 and 31.72 hours under placebo, and the maximum decrease in prothrombin time values after warfarin dosing was 58.75% versus 39.94%. These data demonstrate a CYP2C9-mediated pharmacokinetic interaction with pharmacodynamic, clinically relevant consequences, which might require warfarin dose adjustment.

This report describes novel clinical data assessing the pharmacodynamics of insulin glargine/lixisenatide (iGlarLixi) compared with placebo and insulin glargine alone, to determine pharmacokinetics of lixisenatide, and to assess safety of iGlarLixi in Japanese people with type 2 diabetes mellitus (T2DM). In a single‐centre, open‐label, randomized, placebo‐controlled cross‐over study, participants received subcutaneous iGlarLixi 5 U/5 μg and 10 U/10 μg, placebo, and 5 U insulin glargine. The primary endpoint was area under the postprandial plasma glucose (PPG) curve (AUC0–2h). A total of 20 participants completed all study periods. iGlarLixi 5 U/5 μg and 10 U/10 μg reduced mean PPG dose‐dependently compared with placebo and insulin glargine 5 U. Both combinations significantly reduced PPG‐AUC0–2h dose‐dependently compared with placebo (least squares mean difference −7.48 mmol h/L for 5 U/5 μg, −10.75 mmol h/L for 10 U/10 μg; P < 0.0001). iGlarLixi 5 U/5 μg reduced PPG‐AUC0–2h significantly compared with insulin glargine 5 U (−0.76 mmol h/L; P < 0.0001). No symptomatic hypoglycaemia occurred during the study. iGlarLixi single subcutaneous injections significantly and dose‐dependently reduced PPG compared to placebo or insulin glargine in Japanese participants with T2DM. iGlarLixi was safe and well tolerated, and would be expected to provide the 24‐hour plasma glucose‐lowering effects of insulin glargine and the postprandial antihyperglycaemic effects of lixisenatide.

A pharmacokinetic trial with ticarcillin/clavulanate was undertaken in patients with severe burns. Timentin 5.2 g (ticarcillin 5 g + clavulanate 200 mg) was administered by iv infusion over 20 min, two or three times daily. Fifteen patients with varying amounts of total body surface (TBS) burned could be evaluated for pharmacokinetic calculations (group A, greater than 20% TBS, n = 7; group B, less than 10% TBS, n = 8). Both groups presented similar pharmacokinetic behaviour. Compared with healthy volunteers, the volume of distribution for both ticarcillin and clavulanate was increased 2.5 times. For ticarcillin the mean elimination half-lives in serum were 95.1 (A) and 86.1 min. (B), respectively; for clavulanate, the half-lives were 144.0 (A) and 132.1 min (B), respectively. The 0-8-h urine recovery of ticarcillin was 84% (A) and 83% (B), and for clavulanate it was 86% (A) and 88% (B) of the administered dose. As a consequence of the increased distribution volumes and the increased AUC's in severely burned patients the highest recommended dose of ticarcillin/clavulanate appears suitable.

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