Population pharmacokinetics of recombinant factor VIIa in volunteers anticoagulated with acenocoumarol.
This study establishes a population PK model for FVII clotting activity (FVII:C) after injection of recombinant activated factor VII (rFVIIa) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose ranging from 5 to 320 microg/kg. The FVII:C kinetic was fitted to a 2 compartment model, with continuous "endogenous perfusion" mimicking endogenous activity. Estimated clearance was 2.4 1/h (20% inter-individual variability and 9% inter-period variability). The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively, with 16% inter-individual variability. The dose producing 50% of the maximum drop of INR was estimated to be 2.2 microg/kg. The model will be used to better define the dosage regimen for future clinical developments.
Clinical Pharmacology Unit, EA 643 University Claude Bernard, Hôpital Cardiologique, Lyon, France. PG@upcl.univ-lyon1.fr
P
P
Girard
P
P
Nony
E
E
Erhardtsen
S
S
Delair
P
P
Ffrench
M
M
Dechavanne
J P
JP
Boissel
D000074:Acenocoumarol / Q000627:therapeutic use*; D000925:Anticoagulants / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D015942:Factor VIIa / Q000493:pharmacokinetics*; D006801:Humans; D016015:Logistic Models; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D012016:Reference Values
D000925:Anticoagulants; D011994:Recombinant Proteins; D015942:Factor VIIa; D000074:Acenocoumarol