Comparison of coagulant activity of factor VII and activated factor VII activity assays when used for determination of recombinant activated factor VII levels in plasma.

Two assays [coagulant activity of factor VII (FVII:C) and activated factor VII (FVIIa) activity] are currently available for the assessment of factor VII and FVIIa pharmacokinetics. This article presents the results of a comparison of the two assays when applied both in vitro as well as during clinical pharmacokinetic trials of recombinant FVIIa (rFVIIa) administered to healthy individuals and haemophilia patients. The in-vitro data showed that, for the FVII:C assay, plasma samples do not dilute in parallel. For the FVIIa activity assay, dilutions of samples are both parallel and linear with different dilutions of the calibrator. Moreover, intra-assay variation was found to be smaller for the FVIIa activity assay than for the FVII:C assay. When adding different amounts of rFVIIa (0-6 microg/ml) to normal plasma, a mean specific activity of rFVIIa of 48.6 U/mug was observed on applying the FVII:C assay; however, the specific activity decreased with increasing levels of rFVIIa. For the FVIIa activity assay, the mean specific activity was 45.4 IU/mug. Direct comparison of the two activity assays showed that no simple conversion between FVII:C and FVIIa activity measurements are possible. When applying the two assays for pharmacokinetic assessments in two clinical trials, statistically significant different estimates for the area under the curve, half-life, clearance and volume of distribution were obtained. In conclusion, for evaluation of rFVIIa pharmacokinetic properties, activity should be measured with the FVIIa activity assay - which is a more specific and reliable assay of the two available factor VII activity assays, especially when assessing low activity levels.

Intrasubject variability of inhaled insulin in type 1 diabetes: a comparison with subcutaneous insulin.

We compared intrasubject variability of insulin and glucose profiles after a standardized meal between insulin inhaled via the AERx insulin Diabetes Management System (AERx iDMS, Aradigm Corp., Hayward, CA) and given as a subcutaneous injection. In this single-center, parallel, randomized, open-labeled trial, 17 male, non-smoking patients with type 1 diabetes (mean age, 27.7 years; body mass index, 23.4 kg/m(2)) received a fixed, individualized dose of human insulin, on four treatment days followed by an individualized breakfast, administered either by inhalation via AERx iDMS (n = 9) or by subcutaneous injection. Serum insulin and serum glucose levels were determined at regular intervals for 6 h postdose. Intrasubject variability was expressed as coefficient of variation. No statistically significant differences in intrasubject variability were observed between the treatments for the areas under the insulin curves for 0-6 h [27% vs. 19% (inhaled insulin vs. subcutaneous)] and areas under the glucose curves 0-6 h (30% vs. 23%). Intrasubject variability values for insulin half-life, terminal elimination rate constant, and mean residence time were significantly less in the inhaled insulin group compared with the subcutaneous insulin group (P = 0.01-0.02). Only one potentially trial product-related adverse event (an audible wheeze) was reported, and no clinically relevant changes in pulmonary function were detected. The intrasubject variability was comparable between patients receiving inhaled insulin and subcutaneous insulin, thereby confirming the reproducibility of administering insulin via AERx iDMS. Inhaled insulin was well tolerated and is a feasible alternative to subcutaneous insulin in patients with type 1 diabetes.

Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide.

OBJECTIVE: To investigate if rifampicin is both an inducer and an inhibitor of repaglinide metabolism, it was determined whether the timing of rifampicin co-administration influences the pharmacokinetics of repaglinide. METHODS: Male volunteers ( n=12) participated in a randomised, two-period, crossover trial evaluating the effect of multiple doses of 600 mg rifampicin once daily for 7 days on repaglinide metabolism. Subjects were, after baseline measurements of repaglinide pharmacokinetics, randomised to receive, on either day 7 or day 8 of the rifampicin administration period, a single dose of 4 mg repaglinide and vice versa in the following period. RESULTS: When repaglinide was given, together with the last rifampicin dose, on day 7, an almost 50% reduction of the median repaglinide area under the plasma concentration-time curve (AUC) was observed. Neither the peak plasma concentration (C(max)), time to reach C(max) (t(max)) nor terminal half-life (t(1/2)) was statistically significantly affected. When repaglinide was given on day 8, 24 h after the last rifampicin dose, an almost 80% reduction of the median repaglinide AUC was observed. The median C(max) was now statistically significantly reduced from 35 ng/ml to 7.5 ng/ml. Neither t(max) nor t(1/2) was significantly affected. CONCLUSION: 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.