Population pharmacokinetics of recombinant factor XIII in cynomolgus monkeys.
Hemostasis in humans and other animals is a complex process that controls blood loss after a vascular injury. Factor XIII (FXIII) stabilizes clots primarily by cross-linking fibrin, thus protecting a newly formed clot from fibrinolysis by plasmin. Congenital deficiencies in humans involving FXIII are associated with delayed bleeding and wound healing and severe spontaneous hemorrhaging. These symptoms can be alleviated by intravenous administration of enriched FXIII plasma fractions. Circulating plasma FXIII is found as a heterotetramer that dissociates in the presence of calcium and thrombin into an active dimer and 2 inactive monomers. The recombinant FXIII under investigation is the active dimer alone. A 3-compartment, nonlinear population pharmacokinetic model was implemented in NONMEM V and then used to analyze data from preclinical studies in cynomolgus monkeys. The model simultaneously describes endogenous production of dimer (0.622 microg kg(-1) hr(-1)) and monomer (12.1 microg kg(-1) hr(-1)), and the administration of recombinant dimer. The model incorporates the rate and extent of complexation of recombinant dimer with available endogenous monomer (6.59 mg(-1) kg hr(-1)) to form the heterotetramer. Half-lives for dimer, heterotetramer, and monomer (3.33 hours, 2.83 days, and 3.94 hours for A(2), A(2)B(2), and B, respectively) were estimated, along with their variability in the population studied.
Dodds
Michael G
MG
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Visich
Jennifer E
JE
Vicini
Paolo
P
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008954:Models, Biological; D010599:Pharmacokinetics; D014018:Tissue Distribution
C078147:F8 protein, human; D005169:Factor VIII