When rifampicin and repaglinide are administered concomitantly, rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. After discontinuing rifampicin administration, while the inductive effect on CYP3A4 and probably also CYP2C8 is still present, an even more marked reduction in the plasma concentration of repaglinide was observed. Our results suggest that concomitant administration of rifampicin and repaglinide may cause a clinically relevant decrease in the glucose-lowering effect of repaglinide, in particular when rifampicin treatment is discontinued or if the drugs are not administered simultaneously or within a few hours of each other.

The aim of this open, randomized cross-over study was to compare the efficacy and safety of inhaled budesonide administered either via a pressurized metered dose inhaler with a 750 ml spacer attached, or via a new dry powder inhaler, Turbuhaler, in 28 patients with stable bronchial asthma. During the 2-week run-in period, the patients received their ordinary inhaled steroid treatment. This was followed by two 4-week periods of active treatment with inhaled budesonide given via Turbuhaler or pressurized MDI. The patients were divided into two groups according to their previous, inhaled steroid doses. Group A received 400 micrograms of budesonide b.i.d, and Group B 800 micrograms of budesonide b.i.d. Diary cards were used by the patients at home to report asthma symptoms, beta 2-agonist consumption, and PEF twice daily, as well as the number of coughs experienced in a 5-min period after steroid inhalation. Budesonide Turbuhaler produced a significantly better effect on morning peak flow than budesonide MDI. The number of coughs in the 5 min after steroid inhalation was significantly lower with the Turbuhaler than with the MDI. In all other parameters recorded (e.g. FEV1, evening PEF, histamine PC20 and other diary measurements) there were no statistically significant differences between the two devices. Turbuhaler was significantly more appreciated than MDI in all questions of preference. The study showed that budesonide via Turbuhaler was at least as effective and safe as budesonide via a pressurized MDI at daily doses of 800 and 1,600 micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)

To cite this article: Møss J, Scharling B, Ezban M, Møller Sørensen T. Evaluation of the safety and pharmacokinetics of a fast-acting recombinant FVIIa analogue, NN1731, in healthy male subjects. J Thromb Haemost 2009; 7: 299-305.Summary. Background: NN1731 is a recombinant activated factor VII (rFVIIa) analog with enhanced activity. Objectives: This clinical trial aimed to assess the safety and pharmacokinetics of single doses of NN1731 in healthy male subjects. Methods: This was a randomized, placebo-controlled doseescalation trial with four dose tiers (NN1731 5-30 lg kg). Eight subjects were randomized to either NN1731 (n = 6) or placebo (n = 2) in each tier. Results: No thromboembolic or serious adverse events were reported and no antibody formation towards NN1731 was detected. NN1731 was demonstrated to be pharmacologically active based on coagulation-related parameters (prothrombin fragment 1+2, activated partial thromboplastin time and prothrombin time). There were five mild/moderate adverse events in three subjects. The FVIIa activity of NN1731 after ascending single-dose administration of NN1731 fits well with a two-compartment model, indicating a bi-exponential decline with a rapid initial distribution of approximately 73% FVIIa activity (half-life = 20 min), followed by a less rapid terminal elimination phase eliminating the remaining 27% (half-life = 3 h). Dose proportionality in healthy male subjects at the dose levels investigated (5-30 lg kg . No immunogenic or thromboembolic events were reported. The pharmacokinetic profile of NN1731 as measured by FVIIa activity appears to follow two-compartment pharmacokinetics characterized by an initial rapid distribution phase followed by a less rapid elimination phase.

Recombinant activated factor VIIa (rFVIIa) is a well-established treatment for bleeding episodes in patients with congenital or acquired haemophilia A or B with inhibitors to factors VIII and IX and patients with FVII deficiency. The aim of this trial was to demonstrate bioequivalence between the currently marketed (rFVIIa/NovoSeven) and a new rFVIIa formulation (VII25) stable at up to 25 degrees C. Furthermore, short-term safety and tolerability of VII25 and pharmacokinetics of both formulations were investigated. In this single-centre, randomized, double-blind, two-way cross-over trial, healthy male subjects received one intravenous bolus injection of rFVIIa and one of VII25, both at 90 microg kg(-1), in a randomized order 2-3 weeks apart. Mean VII25/rFVIIa ratio for area under the plasma activity-time curve from time 0 to last quantifiable activity (primary bioequivalence endpoint), was 0.93, 90% confidence interval (CI) (0.89-0.96), within the predefined bioequivalence range (0.80-1.25). Secondary pharmacokinetic parameters were comparable between formulations. No serious adverse events were observed. Six mild or moderate treatment-emergent adverse events were reported in five subjects. Coagulation-related parameter profiles were similar between rFVIIa and VII25. No clinically abnormal changes were observed for laboratory parameters and no subjects developed FVIIa antibodies. This trial demonstrated bioequivalence between the currently available rFVIIa and VII25 stable at up to 25 degrees C. VII25's 'user-friendly' formulation removes the inconvenience of storing/transporting at 2-8 degrees C, and as the drug substance is the same, the activity and safety established for rFVIIa is maintained.

Glanzmann thrombasthenia (GT) is a rare platelet function disorder characterized by a defect in fibrinogen binding to platelet membrane glycoprotein (GP) IIb/IIIa. Recombinant FVIIa (rFVIIa) is a haemostatic agent approved for the treatment of haemophilia patients with inhibitors, patients with acquired haemophilia and in EU also for treatment of factor VII (FVII)-deficient patients and GT patients with antibodies to GPIIb-IIIa. The present study was conducted to evaluate the use of the whole blood test system, rotational thrombelastometry (ROTEM), in measuring the overall haemostasis potential of rFVIIa in 28 GT patients treated with rFVIIa. The correlation of administered rFVIIa and time to start fibrin formation and clot dynamic/stability was assessed and correlation to the clinical response was elucidated. Assessments were performed on predose blood samples spiked with four different concentrations of rFVIIa and whole blood samples taken at 10 and 120 min following dosing. ROTEM parameters clotting time (CT), clot formation time (CFT) and maximum clot firmness (MCF) were measured. Both ex vivo and in vivo data showed beneficial effects on CT in the presence of rFVIIa, but no effect of added rFVIIa was seen on CFT and MCF. In conclusion, the use of thrombelastography at least in the modified form of ROTEM seems to be of limited use in predicting an adequate dose of rFVIIa in GT patients. A good clinical haemostatic response was recorded in spite of the limited changes in the ROTEM pattern supporting the conclusion that ROTEM should not be the method of choice for monitoring rFVIIa therapy in Glanzmann patients.