Pharmacokinetics and safety of FFR-rFVIIa after single doses in healthy subjects.

Erhardtsen E, Nilsson P, Johannessen M, Thomsen MS
J Clin Pharmacol 2001;41(8):880-885.
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Review by : M. Aldouri; J. Ingerslev
NATA Review
This is a double-blind placebo controlled dose escalation trial evaluating efficacy and safety of inactivated rFVIIa (FFR-rFVIIa) as an antithrombotic agent. The trial showed a dose dependent prolongation of the prothrombin time. Future studies in patients undergoing vascular intervention are required.

– M. Aldouri.

FFR-rFVIIa is a variant activated factor VII molecule that is characterised by the inclusion of a tripeptide that is situated at the catalytic site of factor VIII whereby the catalytic function of factor VII is abolished, while its capacity to bind tissue factor (TF) is unchanged.

Therefore, FFR-rFVIIa has a potential to incapacitate the coagulation promoting action of TF. In several pathological conditions intravascular TF is abundantly available to induce local or systemic coagulation on a ruptured arteriosclerotic plaque and in flowing blood in septicaemia where TF is exposed on monocytes.

Authors studied pharmacokinetic behaviour and safety of FFR-rFVIIa in healthy 62 male volunteers in a double-blind, placebo controlled, randomized trial in which volunteers were injected placebo or doses of FFR-rFVIIa ranging 0.1mg/kg b.w. to 0.40 mg/kg b.w.

The pharmacokinetic behaviour of FFR-rFVIIa was linear. The invivo half-life was between 4.9 hours and 5.8 hours following significant doses. The prothrombin time was dose-dependently prolonged following administration of active substance illustrating a TF-dependent anticoagulant activity. The drug was well tolerated, and no test person withdrew. Headache was reported in 5/46 subjects, and mild gingival bleeding occurred in two subejcts within the first 24 hours following active drug administration, and in one person a haematoma at the injection site was noted.

In the concluding remarks authors suggests that future studies should aim at characterizing the possible benefit of FFR-rFVIIa in prevention of re-stenosis in patients undergoing vascular interventions.

– J. Ingerslev.