Allometric scaling and prediction of concentration-time profiles of coagulation factors in humans from animals

Abstract

1. Allometric scaling is a useful tool in early drug development and can be used for the prediction of human pharmacokinetic (PK) parameters from animal PK parameters. The main objective of this work was to predict concentration-time profiles of coagulation factors in humans in a multi-compartment system using animal PK parameters.

2. The prediction of concentration-time profiles in humans in a multi-compartment system was based on the predicted values of clearance and volumes of distribution (V_c, V_ss and V_β) from animals. Five coagulation factors from the literature were chosen that were described by two-compartment model in both humans and animals. Clearance and volumes of distribution from animals were allometrically scaled to humans and then were used to predict concentration-time profiles in humans.

3. The predicted concentration-time profile for a given coagulation factor was accurate for most of the time points. Percent prediction error range varied across coagulation factors. The prediction error >50% was observed either at 1 or a maximum of two time points for a given drug.

4. The study indicated that the allometric scaling can be useful in the prediction of concentration-time profiles of coagulation factors in humans from animals and may be helpful in designing a first-in-human study.     

Air pollution‐associated procoagulant changes: the role of circulating microvesicles

Summary. Background: Epidemiological studies suggest an association between exposure to particulate matter (PM) in air pollution and the risk of venous thromboembolism (VTE). Objectives: To investigate the underlying pathophysiological pathways linking PM exposure and VTE. Patients and methods: We assessed potential associations between PM exposure and coagulation and inflammation parameters, including circulating microvesicles, in a group of 233 patients with diabetes. Results: The numbers of circulating blood platelet‐derived and annexin V‐binding microvesicles were inversely associated with the current levels of PM_2.5 or PM₁₀, measured on the day of sampling. Recent past exposure to PM₁₀, up to 1 week prior to blood sampling, estimated at the patients’ residential addresses, was associated with elevated high‐sensitivity C‐reactive protein (CRP), leukocytes and fibrinogen, as well as with tissue factor (TF)‐dependent procoagulant changes in thrombin generation assays. When longer windows of past exposure were considered, up to 1 year preceding blood sampling, procoagulant changes were evident from the strongly increased numbers of red blood cell‐derived circulating microvesicles and annexin V‐binding microvesicles, but they no longer associated with TF. Past PM exposure was never associated with activated partial thromboplastin time (aPTT), prothrombin time (PT), or factor (F) VII, FVIII, FXII or D‐dimers. Residential distance to a major road was only marginally correlated with procoagulant changes in FVIII and thrombin generation. Conclusions: Increases in the number of microvesicles and in their procoagulant properties, rather than increases in coagulation factors per se, seem to contribute to the risk of VTE, developing during prolonged exposure to air pollutants.     

局麻单孔腹腔镜双极电凝与经腹近端抽芯包埋两种输卵管绝育术对生殖激素近期影响的对比观察

目的:比较观察局麻单孔腹腔镜双极电凝输卵管绝育术与经腹近端抽芯包埋输卵管绝育术对卵巢功能的影响。方法:在贵州省内14个县随机抽取2014年10月~2015年10月行上述两种输卵管绝育术妇女各100例,测定卵巢基础激素(FSH、LH和E2)。结果:共133例研究对象进入观察,其中腹腔镜输卵管绝育术组82名,年龄28.84±4.02岁;开腹输卵管绝育术组51名,年龄27.61±4.20岁。两组术后1个月的卵巢基础性激素平均水平无统计学改变;术后1个月基础FSH≥10U/L、基础FSH/LH升高2的比例开腹组明显高于腹腔镜组。结论:腹腔镜输卵管绝育术近期对卵巢功能的影响小于开腹输卵管绝育术。     

Comparison of the efficacy of two human fibrinogen concentrates to treat dilutional coagulopathy in vitro

Both congenital and acquired fibrinogen deficiency can be safely treated with administration of fibrinogen concentrate.

The aim of this study was to test the efficacy of a new fibrinogen product (Fibryga) compared to a licensed product (Haemocomplettan) in an in vitro model of dilutional coagulopathy.

Ten blood specimens from healthy volunteers were diluted 1:1 with balanced crystalloid solution and subsequently supplemented with each fibrinogen concentrate at a dose replicating in vivo supplementation (50?mg kg^?1). Changes in clot firmness (FIBTEM and EXTEM assay), as well as changes in the fibrinogen antigen level, fibrinogen activity, factor XIII level and fibronectin levels were assessed at baseline, after dilution and after adding fibrinogen concentrate.

There was no significant difference between the drugs in their in vitro ability to improve clot firmness in the FIBTEM assay (Fibryga: mean MCF 14.4?mm (SD 3.4?mm) vs. Haemocomplettan: MCF 14.1?mm (2.4); p?=?.584). Fibryga led to significantly higher clot firmness in EXTEM MCF: 56.7?mm (3.8) vs. 53.7?mm (3.7); p?p??1 (SD 0.002?g L^?1) vs. 0.002?g L^?1 (SD 0.002?g L^?1; p?This is the first study to demonstrate that Fibryga and Haemocomplettan have similar efficacy in improving clot firmness in a dilutional hypofibrinogenemia model in vitro.