Real-Life Population Pharmacokinetics of Recombinant Factor XIII and Dosing Considerations for Preventing the Risk of Bleeding in Patients with FXIII Congenital Deficiency.
Journal
Clinical pharmacokinetics
ISSN: 1179-1926
Titre abrégé: Clin Pharmacokinet
Pays: Switzerland
ID NLM: 7606849
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
accepted:
03
10
2021
pubmed:
1
11
2021
medline:
6
4
2022
entrez:
31
10
2021
Statut:
ppublish
Résumé
Recombinant factor XIII (rFXIII) at the recommended dosage of 35 IU/kg every 4 weeks is currently used for prophylaxis of bleeding in patients affected by FXIII deficiency. The aim of this study was to describe the population pharmacokinetics of rFXIII in patients with FXIII deficiency being treated with rFXIII in real-life and to assess, using Monte Carlo simulations, the attainment of defined FXIII concentration thresholds associated with prevention of the risk of bleeding over time. A nonlinear mixed-effects model approach was used for population analysis. Monte Carlo simulations were used to generate 10,000 FXIII concentration-time profiles associated with incremental doses of 25, 30, 35, 40, 45 and 50 IU/kg of rFXIII. The probability of target attainment (PTA) of FXIII concentrations at thresholds of > 0.05, > 0.10 and > 0.15 IU/mL were calculated weekly, from days 7 to 49. A total of 18 patients provided 99 FXIII concentrations; most patients (77.8%, 14/18) had severe FXIII deficiency. A two-compartment pharmacokinetic model with linear elimination from the central compartment best described rFXIII data. No covariates were associated with rFXIII disposition. Pharmacokinetic parameter estimates were 0.16 mL/h/kg for clearance, 57.35 mL/kg for volume of distribution at steady-state, and 11.72 days for elimination half-life. The standard 35 IU/kg dose resulted in PTAs of the pharmacodynamic thresholds of FXIII concentrations of > 0.05, > 0.10 and > 0.15 IU/mL at day 28 that were equal to 89.9%, 68.9% and 47.8%, respectively. Intensive FXIII monitoring from day 14, and/or shortening the dosing interval between rFXIII administrations, should be considered to minimise the risk of bleeding.
Sections du résumé
BACKGROUND AND OBJECTIVE
Recombinant factor XIII (rFXIII) at the recommended dosage of 35 IU/kg every 4 weeks is currently used for prophylaxis of bleeding in patients affected by FXIII deficiency. The aim of this study was to describe the population pharmacokinetics of rFXIII in patients with FXIII deficiency being treated with rFXIII in real-life and to assess, using Monte Carlo simulations, the attainment of defined FXIII concentration thresholds associated with prevention of the risk of bleeding over time.
METHODS
A nonlinear mixed-effects model approach was used for population analysis. Monte Carlo simulations were used to generate 10,000 FXIII concentration-time profiles associated with incremental doses of 25, 30, 35, 40, 45 and 50 IU/kg of rFXIII. The probability of target attainment (PTA) of FXIII concentrations at thresholds of > 0.05, > 0.10 and > 0.15 IU/mL were calculated weekly, from days 7 to 49.
RESULTS
A total of 18 patients provided 99 FXIII concentrations; most patients (77.8%, 14/18) had severe FXIII deficiency. A two-compartment pharmacokinetic model with linear elimination from the central compartment best described rFXIII data. No covariates were associated with rFXIII disposition. Pharmacokinetic parameter estimates were 0.16 mL/h/kg for clearance, 57.35 mL/kg for volume of distribution at steady-state, and 11.72 days for elimination half-life. The standard 35 IU/kg dose resulted in PTAs of the pharmacodynamic thresholds of FXIII concentrations of > 0.05, > 0.10 and > 0.15 IU/mL at day 28 that were equal to 89.9%, 68.9% and 47.8%, respectively.
CONCLUSIONS
Intensive FXIII monitoring from day 14, and/or shortening the dosing interval between rFXIII administrations, should be considered to minimise the risk of bleeding.
Identifiants
pubmed: 34718987
doi: 10.1007/s40262-021-01079-x
pii: 10.1007/s40262-021-01079-x
doi:
Substances chimiques
Recombinant Proteins
0
Factor XIII
9013-56-3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
505-513Investigateurs
Laura Banov
(L)
Chiara Biasioli
(C)
Patrizia Di Gregorio
(P)
Antonietta Ferretti
(A)
Angelo Claudio Molinari
(AC)
Lucia Dora Notarangelo
(LD)
Roberta Palla
(R)
Flora Peyvandi
(F)
Michele Pizzuti
(M)
Berardino Pollio
(B)
Gianluca Sottilotta
(G)
Simona Maria Siboni
(SM)
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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