Coagulation factor X Other names: Stuart-Prower factor Prothrombinase

Factor X is an inactive zymogen, which can be activated by factor IXa (via the intrinsic pathway) or by factor VIIa (via the extrinsic pathway). Factor X is converted from its inactive form to the active form (factor Xa) by the cleavage of a 52-residue peptide from the heavy chain. Factor Xa associates with factor Va on a phospholipid surface to form the prothrombinase complex, which activates prothrombin to thrombin in the presence of calcium ions. Thrombin then acts upon soluble fibrinogen and factor XIII to generate a crosslinked fibrin clot.

Pharmacodynamic effects

Coagulation factor X is derived from human plasma and used as a replacement for the naturally existing coagulation factor X in patients with hereditary factor X deficiency.

In a clinical study of coagulation factor X in subjects with severe or moderate factor X deficiency (basal FX:C <5 IU/dL), the pharmacokinetics of coagulation factor X were assessed in 16 subjects after administration of a nominal dose of 25 IU/kg. Pharmacokinetic (PK) parameters were calculated from plasma factor X:C (one-stage clotting assay) activity measurements after subtraction of the pre-dose value. Combining IR values for FX:C at the baseline visit (n=16) and the Repeat PK assessment (n=15) gave an overall geometric mean IR of 2.07 IU/dL per IU/kg administered (n=31). Similarly, combining t_½ values at the Baseline Visit and the Repeat PK assessment gave an overall geometric mean t_½ of 29.36 hours. Systemic exposure to FX:C at the Repeat PK visit (at least 6 months later) was equivalent to that at baseline, since repeat/baseline ratios for all PK parameters were within the range of 90% to 110%.

The mean (CV%) for incremental recovery was 2.08 (18.1). The mean (CV%) maximum plasma concentration (C_max) was 0.504 (17.2) IU/mL.

The mean (CV%) for area under the curve (AUC_0-144h) was 17.1 (21.0) IU.hr/mL.

Human coagulation factor X is largely retained within the vascular compartment: mean apparent volume of distribution (V_ss) was 56.3 (24.0) mL/kg.

The mean (CV%) half-life of human coagulation factor X was 30.3 (22.8) hr and clearance was 1.35 (21.7) mL/kg/hr.

Renal impairment

No pharmacokinetic studies have been conducted but there is no anticipated effect of gender or renal function on the pharmacokinetic profile of coagulation factor X.

Hepatic impairment

No pharmacokinetic studies have been conducted but there is no anticipated effect of gender or hepatic function on the pharmacokinetic profile of coagulation factor X.

Elderly

No pharmacokinetic studies have been conducted but there is no anticipated effect of age on the pharmacokinetic profile of coagulation factor X.

Paediatric population

Pharmacokinetic studies have not been performed in children under the age of 12 years. The study in young children measured incremental recovery at 30 min (IR_30min) after the first dose and after the last dose in the study (approximately 6 months later). Combining IR_30min values for FX:C at the baseline visit (n=9) and the Repeat PK assessment (n=9) gave an overall geometric mean IR of 1.74 (range 1.3-2.2) IU/dL per IU/kg administered (n=9). For the subgroup aged 6-11 years (n=5), the geometric mean IR_30min was 1.91 (range 1.6 -2.2) IU/mL per IU/kg and for the youngest subgroup, 0-5 years (n=4) was 1.53range 1.3-1.8) IU/mL per IU/kg.

Trough levels of FX:C were measured during the first 6 weeks of the study to individualise the dosage regimen and to maintain a trough level of at least 5 IU/dL. During the dose-adjustment phase, two trough levels were <5 IU/dL but thereafter none were below this threshold.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeat-dose toxicity, thrombogenicity and local tolerability.

No investigations on genotoxicity, carcinogenicity and reproductive or developmental toxitcity have been conducted since human plasma coagulation factor X is an endogenous protein.