Population pharmacokinetics of a triple-secured fibrinogen concentrate administered to afibrinogenaemic patients: Observed age- and body weight-related differences and consequences for dose adjustment in children

Abstract

Aims: The pharmacokinetics (PK) of a triple-secured fibrinogen concentrate (FC) was assessed in patients ≥40 kg by noncompartmental analysis over a period of 14 days with multiple blood samples. Limited PK time point assessments in children lead to consideration of using Bayesian estimation for paediatric data. The objectives were (i) to define the population PK of FC in patients with afibrinogenaemia; (ii) to detect age- and body weight-related differences and consequences for dose adjustment.

Methods: A population PK model was built using plasma fibrinogen activity data collected in 31 patients aged 1 to 48 years who had participated in a single-dose PK study with FC 0.06 g kg^-1 .

Results: A 1-compartment model with allometric scaling accounting for body weight was found to best describe the kinetics of FC. Addition of age and sex as covariates did not improve the model. Incremental in vivo recovery assessed at the end of infusion with the predicted maximal concentrations was lower, weight-adjusted clearance was higher, and fibrinogen elimination half-life was shorter in patients <40 kg than patients ≥40 kg. Interpatient variability was similar in both groups.

Conclusion: Dosing in patients ≥40 kg based on the previous empirical finding using noncompartmental analysis where FC 1 g kg^-1 raises the plasma fibrinogen activity by 23 g L^-1 was confirmed. In patients <40 kg, (covering the age range from birth up to about 12 years old) FC 1 g kg^-1 raises the plasma fibrinogen by 19 g L^-1 . Dosing should be adapted accordingly unless therapy is individualized.

Keywords: coagulation, congenital disorders, NONMEM, paediatrics, population analysis.

Figure 1

Mean (standard deviation) values of fibrinogen plasma activity over time stratified by body weight

Figure 2

Visual predictive check plot for the final FC activity population pharmacokinetic population model for the entire population and stratified by body weight: (A) subjects <40 kg and (B) subjects ≥40 kg. In total, 2000 simulations were performed per virtual subject. Dotted lines represent quantiles Q95 and Q5 of the observed values; full line represents the Q50. Grey shaded areas are 95% confidence intervals of simulated 5th, 50th and 95th percentiles

Figure 3

Forest plots of the incremental recovery at Tmax for fibrinogen activity comparing patients <40 kg with patients ≥40 kg. The dot corresponds to the mean. The left vertical line corresponds to 2.5% of confidence interval (CI); the right vertical line corresponds to 97.5% of CI

Figure 4

Correlation between fibrinogen antigen and fibrinogen activity concentrations for all clinical samples from all clinical studies