ABSTRACT
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.
Subject(s)
Blood Coagulation Tests/methods , Factor VII Deficiency/blood , Factor VII Deficiency/drug therapy , Factor VII/metabolism , Adolescent , Adult , Blood Coagulation/drug effects , Blood Coagulation/physiology , Child , Child, Preschool , Coagulants/metabolism , Factor VII/chemistry , Factor VII/pharmacology , Factor VIIa , Hemophilia A/drug therapy , Hemophilia A/metabolism , Humans , Male , Middle Aged , Plasma/chemistry , Plasma/metabolism , Recombinant Proteins/blood , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacology , Reference Values , Thromboplastin/metabolismABSTRACT
We wanted to establish a minipig model for the study of postprandial lipemia and plasma lipid clearance after fish oil consumption. Seven minipigs were fed a fish oil-enriched nonpurified diet and a control diet for 4 wk in a randomized cross-over study. After each intervention period, each pig was challenged with a gastric fat load (2 g fat/kg body) and an intravenous fat bolus (0.1 g/kg body) on separate days. Frequent blood samples were collected for 6 h after the gastric fat load and for 40 min after the intravenous bolus. The fish oil-enriched diet was associated with lower triacylglycerol, glycerol and nonesterified fatty acid concentrations in the hours after the gastric fat load than the control diet (P < 0.05). In contrast, the triacylglycerol disappearance rate after the intravenous fat bolus was not affected by fish oil (P = 0.19). In conclusion, dietary fish oil supplementation attenuates postprandial lipemia in minipigs similarly to what occurs in humans. Minipigs could serve as a useful model for future studies of this phenomenon. We observed no significant effect of fish oil supplementation on plasma triacylglycerol clearance and thus were unable to identify the mechanism explaining the attenuated lipemia in minipigs.
