Perspective – The case for zero bleeds and drug bioequivalence in the treatment of congenital hemophilia A in 2021

Alessandro Di Minno, Gaia Spadarella, Salvatore Esposito, Prasad Mathew, Giovanni Di Minno, Pier Mannuccio Mannucci

Research output: Contribution to journalReview articlepeer-review

Abstract

Not all patients with severe hemophilia A (HA) respond optimally to a given dose of a given product. Within-individual variance in cross-over studies makes each patient unique in the response to each standard half-life (SHL) factor VIII (FVIII) product in pharmacokinetic (PK) terms. This hampers the prediction of efficacy when a SHL FVIII product is employed. PK data showing that half-lives of SHL rFVIII are unsatisfactory to achieve zero bleeding in individual HA patients provide the rationale for switching from SHL to extended half-life (EHL) products. However, not all subjects receiving prophylaxis with EHL products achieve zero bleeding, the most cogent objective of personalized prophylaxis. Known determinants of FVIII half-life (age, von Willebrand factor [VWF] levels, blood group) cumulatively account for one third of the total inter-individual variation in FVIII clearance in subjects with severe HA. Investigations into precision, and accuracy of laboratory measurement to be employed; newer pathways for the clearance of both free-FVIII and VWF-bound FVIII, and adequately powered studies on omics and phenotypic heterogeneity, are likely to provide additional information on the remaining two thirds of inter-individual variation in FVIII clearance in HA. Variability in the clinical response has also been documented in patients when FVIII activity is mimicked by fixed subcutaneous doses of the bispecific antibody emicizumab. National registries that collect PK data of available FVIII products and ad hoc information on the individual response to emicizumab should be encouraged, to establish newer standards of care and ease personalized clinical decisions to achieve zero bleeding.

Original languageEnglish
Article number100849
JournalBlood Reviews
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • Bioequivalence
  • Emicizumab
  • Extended half-life FVIII products
  • HA and B
  • Monogenic disorder
  • Newer determinants of FVIII half-life
  • Phenotypic heterogeneity of patients
  • Standard half-life FVIII products
  • Tailored prophylaxis
  • Zero bleeding

ASJC Scopus subject areas

  • Hematology
  • Oncology

Fingerprint

Dive into the research topics of 'Perspective – The case for zero bleeds and drug bioequivalence in the treatment of congenital hemophilia A in 2021'. Together they form a unique fingerprint.

Cite this