Michael G Dodds(1), Paolo Vicini(1), Jennifer E Visich(2) and Mark Rogge(2)
(1) Department of Bioengineering, University of Washington, Seattle, Washington, USA (2) ZymoGenetics Inc., Seattle, Washington, USA
Purpose: To develop a population pharmacokinetic model to describe the fate of recombinant FXIII-A2 (rA2) subunit administered to patients congenitally deficient (CD) in Factor XIII A2 subunit. The model incorporates the rate and extent of complexation of recombinant A2 (rA2) with available endogenous FXIII-B subunit to form the heterotetramer, rA2B2. Circulating FXIII is activated by calcium and thrombin, and the A2 subunit is liberated, activated and is responsible for cross-linking fibrin and stabilizing clots.
Methods: Previously, a three-compartment, nonlinear population PK model was implemented in NONMEM V, and then used to analyze data from randomized, double-blind, placebo controlled Phase I studies of rA2 in healthy volunteers. Immunoassay data included plasma levels for FXIII activity and A2B2, total A2 and free B concentrations. This model was extended to include a genetic covariate (FXIII A subunit deficient or normal) and differences in assay matrix composition. Phase I studies in CD subjects were then assessed using this model.
Results: The half-life of FXIII was found to be similar in healthy volunteers and CD subjects. Endogenous production rates of FXIII-B subunit were unchanged, but endogenous production of A2 in CD patients was estimated to be very small, as expected. Assay scale factors, in the form of volume of distribution, were found to be different in CD subjects.
Conclusions: The model well described immunoassay data prior to and following single- and multiple-dose administration of rA2 and its subsequent incorporation into rA2B2 in both healthy and CD subjects. This mechanistic model can be used for prospective simulation of other dosing schemes and modified to account for both congenital and potentially acquired FXIII deficiencies.
Reference: PAGE 13 (2004) Abstr 506 [www.page-meeting.org/?abstract=506]
Poster: poster