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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.

SUBMITTER: Bellon A

PROVIDER: S-EPMC7015754 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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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.

Bellon Anne A Fuseau Eliane E Roumanie Olivier O Lamazure Jennifer J Stevens Wil W Dahmane Amel A Barthez-Toullec Malika M Golly Dominique D Henriet Céline C Bridey Françoise F

British journal of clinical pharmacology 20200109 2

<h4>Aims</h4>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 adjus ...[more]

PMID: 31658379

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Project description:BACKGROUND:Hypofibrinogenaemia is associated with increased morbidity and mortality, but the optimal treatment level, the use of preemptive treatment and the preferred source of fibrinogen remain disputed. Fibrinogen concentrate is increasingly used and recommended for bleeding with acquired haemostatic deficiencies in several countries, but evidence is lacking regarding indications, dosing, efficacy and safety. OBJECTIVES:We assessed the benefits and harms of fibrinogen concentrate compared with placebo or usual treatment for bleeding patients. SEARCH METHODS:We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8); MEDLINE (1950 to 9 August 2013); EMBASE (1980 to 9 August 2013); International Web of Science (1964 to 9 August 2013); CINAHL (1980 to 9 August 2013); LILACS (1982 to 9 August 2013); and the Chinese Biomedical Literature Database (up to 10 November 2011), together with databases of ongoing trials. We contacted trial authors, authors of previous reviews and manufacturers in the field. SELECTION CRITERIA:We included all randomized controlled trials (RCTs), irrespective of blinding or language, that compared fibrinogen concentrate with placebo/other treatment or no treatment in bleeding patients, excluding neonates and patients with hereditary bleeding disorders. DATA COLLECTION AND ANALYSIS:Three review authors independently abstracted data; we resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effects of fibrinogen concentrate in adults and children in terms of various clinical and physiological outcomes. We presented pooled estimates of the effects of intervention on dichotomous outcomes as risk ratios (RRs) and on continuous outcomes as mean differences, with 95% confidence intervals (CIs). We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis. MAIN RESULTS:We included six RCTs with a total of 248 participants; none of the trials were determined to have overall low risk of bias. We found 12 ongoing trials, from which we were unable to retrieve any data. Only two trials provided data on mortality, and one was a zero event study; thus the meta-analysis showed no statistically significant effect on overall mortality (2.6% vs 9.5%, RR 0.28, 95% CI 0.03 to 2.33). Our analyses on blood transfusion data suggest a beneficial effect of fibrinogen concentrate in reducing the incidence of allogenic transfusions (RR 0.47, 95% CI 0.31 to 0.72) but show no effect on other predefined outcomes, including adverse events such as thrombotic episodes. AUTHORS' CONCLUSIONS:In the six available RCTs of elective surgery, fibrinogen concentrate appears to reduce transfusion requirements, but the included trials are of low quality with high risk of bias and are underpowered to detect mortality, benefit or harm. Furthermore, data on mortality are lacking, heterogeneity is high and acute or severe bleeding in a non-elective surgical setting remains unexplored. Currently, weak evidence supports the use of fibrinogen concentrate in bleeding patients, as tested here in primarily elective cardiac surgery. More research is urgently needed.

Dataset Information

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.

Publications

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.

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