A study of the pharmacokinetics and safety of recombinant activated factor VII in healthy Caucasian and Japanese subjects

Abstract

In this randomized, placebo-controlled, double-blind, single-centre, dose escalation study, we report the first evaluation of the pharmacokinetics and safety of recombinant activated factor VII (rFVIIa) in healthy Caucasian and Japanese subjects. Thirty-two healthy subjects were stratified according to sex and ethnic group to receive single bolus intravenous injections of three different doses of rFVIIa (40, 80, 160 microg/kg rFVIIa) or placebo, each separated by a 7-day wash-out period. Blood samples were taken up to 24 h after dosing. The factor VII clotting activity appeared to be dose dependent, but independent of sex and ethnic group. Statistical analyses demonstrated no significant effect of dose, sex or ethnicity on the dose-normalized mean area under the plasma concentration-time curve AUC0-t, indicating dose proportionality. No serious adverse events or thromboembolic events were reported. Analyses of coagulation parameters did not suggest induction of systemic coagulation when dosing rFVIIa up to 160 microg/kg. In conclusion, the pharmacokinetics of rFVIIa in Caucasian and Japanese subjects are similar, and no safety issues were identified.

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“…In theory, if a trauma patient had no post-dose RBC requirement, the estimated clearance of rFVIIa would be 36 ml.kg -1 .h -1 and the terminal half-life would be 2.6 hours. These estimates are in good agreement with non-compartment and population analysis results reported in (non-bleeding) healthy volunteers [20,21]. However with an RBC requirement of 40 units, clearance almost doubles to 62 ml.kg -1 .h -1 while the half life is shortened by nearly one hour to 1.7 hours.…”

Safety and pharmacokinetics of a recombinant fusion protein linking coagulation factor VIIa with albumin in healthy volunteers

“…). D‐dimers, F 1 + 2 fragments, and TAT are markers of thrombin generation, and a transient increase of similar magnitude and duration has been published previously in studies investigating rFVIIa, N7‐GP, and vatreptacog alpha in healthy volunteers . A dose dependency could not be established.…”

A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

“…This linear PK profile enables accurate prediction of plasma ACE910 concentration according to dose. Notably, the mean half-life of ACE910 ranged between 28.3 and 34.4 days, dramatically longer than current drugs (FVIII agents: 8-12 hours 1 ; rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [TG-based half-life] 13 ) and drugs recently approved or under development (#19 hours). 5,[21][22][23][24] Concizumab is a humanized anti-tissue factor pathway inhibitor antibody and is also subcutaneously available in humans.…”

“…1 Patients who develop FVIII inhibitors are treated with bypassing agents, including recombinant activated factor VII (rFVIIa) 7 or activated prothrombin complex concentrate (aPCC). 8 Frequent intravenous administration of these agents is required because of their unstable hemostatic efficacy caused by short half-lives (rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [thrombin generation (TG)-based half-life] 13 ). New treatments with more convenient administration routes, lower administration frequency, and less immunogenicity against coagulation factors are needed.…”