Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis

Purpose Knowledge of the pharmacokinetics (PK) of plasma-derived factor IX (FIX) is still inadequate, with conflicting findings on its elimination half-life and as yet no analysis of the variance in PK between and within individuals. The aim of the study was thus to characterize the PK of plasma-derived FIX, including estimates of variance between and within patients, in adult patients and to predict the variation between individuals in dose requirement to produce a target trough level during regular prophylaxis. Methods Plasma FIX versus time data were compiled from four published and one unpublished PK study involving a total of 26 adult patients with severe haemophilia B. The number of PK assessments per patient varied between one and eight, yielding in total 893 measured FIX levels from 80 study occasions. A population PK model was developed to describe the whole dataset. Parameter values from the model were used to calculate the dose requirement to maintain a trough level of 1% of normal FIX activity in each patient. Results The disposition of FIX was well described by a three-compartment PK model. The median elimination half-life was 31 h, and the variation between individuals was modest both in PK and in dose requirement during twice-weekly prophylaxis. Conclusion With twice weekly dosing, the need for PK-based dose tailoring of FIX in adult patients appears to be limited. However, monitoring FIX levels should be considered in children, in patients who do not respond satisfactorily to standard dosing, and if treatment is switched from plasma-derived to recombinant FIX.