Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII

C. Hermans, J. Mahlangu, J. Booth, H. Schütz, E. Santagostino, G. Young, H. Y. Lee, K. N. Steinitz-Trost, V. Blanchette, E. Berntorp

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Abstract

Introduction: Currently, no universally accepted definition of extended half-life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half-life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. Aim: To identify the half-life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. Methods: A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always >1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half-life was extended until the percentage of patients with FVIII >1 IU/dL equalled that of the benchmark regimen. Results: Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half-life extensions required to maintain 56.6% of patients at FVIII levels >1 IU/dL were 1.30 and 1.26, respectively. A half-life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII >1 IU/dL. Conclusion: Based on this investigation, EHL rFVIII products should have a minimum half-life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.

Original languageEnglish
Pages (from-to)376-384
JournalHaemophilia
Volume24
Issue number3
DOIs
Publication statusPublished - 2018

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Keywords

  • Administration and dosage
  • Factor VIII
  • Haemophilia A
  • Half-life
  • Pharmacokinetics
  • Quality of life

ASJC Scopus subject areas

  • Hematology
  • Genetics(clinical)

Cite this

Hermans, C., Mahlangu, J., Booth, J., Schütz, H., Santagostino, E., Young, G., Lee, H. Y., Steinitz-Trost, K. N., Blanchette, V., & Berntorp, E. (2018). Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII. Haemophilia, 24(3), 376-384. https://doi.org/10.1111/hae.13483