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Pharmacokinetics of perioperative FVIII in adult patients with haemophilia A: An external validation and development of an alternative population pharmacokinetic model.

Publication ,  Journal Article
Zhu, J; Wu, YS; Beechinor, RJ; Kemper, R; Bukkems, LH; Mathôt, RAA; Cnossen, MH; Gonzalez, D; Chen, S-L; Key, NS; Crona, DJ
Published in: Haemophilia
November 2021

INTRODUCTION: Haemophilia A patients require perioperative clotting factor replacement to limit excessive bleeding. Weight-based dosing of Factor VIII (FVIII) does not account for inter-individual pharmacokinetic (PK) variability, and may lead to suboptimal FVIII exposure. AIM: To perform an external validation of a previously developed population PK (popPK) model of perioperative FVIII in haemophilia A patients. METHODS: A retrospective chart review identified perioperative haemophilia A patients at the University of North Carolina (UNC) between April 2014 and November 2019. Patient data was used to externally validate a previously published popPK model proposed by Hazendonk. Based on these validation results, a modified popPK model was developed to characterize FVIII PK in our patients. Dosing simulations were performed using this model to compare FVIII target attainment between intermittent bolus (IB) and continuous infusion (CI) administration methods. RESULTS: A total of 521 FVIII concentrations, drawn from 34 patients, were analysed. Validation analyses revealed that the Hazendonk model did not fully capture FVIII PK in the UNC cohort. Therefore, a modified one-compartment model, with weight and age as covariates on clearance (CL), was developed. Dosing simulations revealed that CI resulted in improved target attainment by 16%, with reduced overall FVIII usage by 58 IU/kg, compared to IB. CONCLUSION: External validation revealed a previously published popPK model of FVIII did not adequately characterize UNC patients, likely due to differences in patient populations. Future prospective studies are needed to evaluate our model prior to implementation into clinical practice.

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Published In

Haemophilia

DOI

EISSN

1365-2516

Publication Date

November 2021

Volume

27

Issue

6

Start / End Page

974 / 983

Location

England

Related Subject Headings

  • Retrospective Studies
  • Humans
  • Hemostatics
  • Hemorrhage
  • Hemophilia A
  • Factor VIII
  • Cardiovascular System & Hematology
  • Adult
  • 3202 Clinical sciences
  • 1103 Clinical Sciences
 

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Zhu, J., Wu, Y. S., Beechinor, R. J., Kemper, R., Bukkems, L. H., Mathôt, R. A. A., … Crona, D. J. (2021). Pharmacokinetics of perioperative FVIII in adult patients with haemophilia A: An external validation and development of an alternative population pharmacokinetic model. Haemophilia, 27(6), 974–983. https://doi.org/10.1111/hae.14393
Zhu, Jing, Yi Shuan Wu, Ryan J. Beechinor, Ryan Kemper, Laura H. Bukkems, Ron A. A. Mathôt, Marjon H. Cnossen, et al. “Pharmacokinetics of perioperative FVIII in adult patients with haemophilia A: An external validation and development of an alternative population pharmacokinetic model.Haemophilia 27, no. 6 (November 2021): 974–83. https://doi.org/10.1111/hae.14393.
Zhu J, Wu YS, Beechinor RJ, Kemper R, Bukkems LH, Mathôt RAA, Cnossen MH, Gonzalez D, Chen S-L, Key NS, Crona DJ. Pharmacokinetics of perioperative FVIII in adult patients with haemophilia A: An external validation and development of an alternative population pharmacokinetic model. Haemophilia. 2021 Nov;27(6):974–983.
Journal cover image

Published In

Haemophilia

DOI

EISSN

1365-2516

Publication Date

November 2021

Volume

27

Issue

6

Start / End Page

974 / 983

Location

England

Related Subject Headings

  • Retrospective Studies
  • Humans
  • Hemostatics
  • Hemorrhage
  • Hemophilia A
  • Factor VIII
  • Cardiovascular System & Hematology
  • Adult
  • 3202 Clinical sciences
  • 1103 Clinical Sciences