Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

• Published in: Pharmaceutics Vol. 12; no. 4; p. 380
• Main Authors: Allard, Quentin, Djerada, Zoubir, Pouplard, Claire, Repessé, Yohann, Desprez, Dominique, Galinat, Hubert, Frotscher, Birgit, Berger, Claire, Harroche, Annie, Ryman, Anne, Flaujac, Claire, Chamouni, Pierre, Guillet, Benoît, Volot, Fabienne, Szymezak, Jean, Nguyen, Philippe, Cazaubon, Yoann
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.04.2020; MDPI
• Subjects: Blood groups; Datasets; dose tailoring; factor VIII; Hematology; Hemophilia; Human health and pathology; Life Sciences; modelling; Patients; Pharmaceutical sciences; Pharmacokinetics; Pharmacology; Population; severe haemophilia A; Software; switch; pharmacokinetics; severe haemophilia A; dose tailoring; factor VIII; modelling; switch
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics12040380

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.