Pharmacokinetics of factor IX in patients with haemophilia B. Methodological aspects and physiological interpretation.
The aims of this study were to investigate the influence of total blood sampling time on the estimated pharmacokinetic parameters of Factor IX procoagulant activity (FIX:C) and to relate the pharmacokinetics of FIX:C to the putative physiological disposition of Factor IX (FIX). Six patients with severe haemophilia B each received 2 infusions of FIX and on both occasions blood samples were collected for 104 h. Each FIX:C decay curve was processed with successive deletion of the last (remaining) datapoint. The fitted terminal half-life (t1/2 beta) and the calculated model-independent mean residence time (MRTMI), elimination clearance (CLMI) and volume of distribution at steady state (Vss) stabilised close to their final values when FIX:C data corresponding to at least 56 h of sampling were used. The final mean values were t1/2 beta = 34 h, MRTMI = 37 h, CLMI = 4.0 ml.h-1.kg-1 and Vss = 0.15 l.kg-1. The disposition of FIX could be characterised by a two-compartment pharmacokinetic model. On average, FIX molecules spent 44% of their total MRT in the second (or "extravascular") compartment. The distribution clearance was comparable to estimated total lymph flow. The volume of the central compartment was twice the estimated plasma volume, which may reflect the rapid and reversible binding of FIX to vascular endothelium. This explains the common clinical finding that the peak activity of FIX:C is less than the injected dose divided by the estimated plasma volume of the patient.
Björkman
S
S
Hospital Pharmacy, Malmö General Hospital, Sweden.
Carlsson
M
M
Berntorp
E
E
D001800:Blood Specimen Collection; D005164:Factor IX / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002836:Hemophilia B / Q000097:blood*; D006801:Humans; D007262:Infusions, Intravenous; D008954:Models, Biological; D013997:Time Factors
D005164:Factor IX