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?

Abstract

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.

Influence of blood group and von Willebrand factor on population pharmacokinetics and dose individualization of recombinant factor VIII in Taiwanese patients with haemophilia A

“…The estimated CL in a 66.7 kg patient was 1.74 dL/h, which is within the range reported by other studies (1.51-2.76 dL/h). [7][8][9][10][13][14][15][16]21,22] The estimated terminal half-life of 13.35 h is comparable to the values previously reported in recombinant, full length FVIII (11.69-13.79 h) (Supplementary Table 1). [7,9,10,21] Additionally, our estimated clearance and half-life was consistent with the values obtained from Japanese patients.…”

Population pharmacokinetic modeling of factor concentrates in hemophilia: an overview and evaluation of best practice

“…Of these 20, 6 combined data of multiple concentrates. 11,[18][19][20][21][22] Eleven publications described a population PK model for a SHL FVIII concentrate, 8 publications for an EHL FVIII concentrate, and 1 publication for both SHL and EHL FVIII concentrates.…”

An Algorithm for Nonparametric Estimation of a Multivariate Mixing Distribution with Applications to Population Pharmacokinetics

“…Ishihara et al [ 40 ] and Soraluce et al [ 41 ] use the industry standard parametric version of NONMEM. Allard et al [ 42 ] uses the stochastic approximation expectation maximization method (SAEM). NPAG can run any problem that is run by any of these programs.…”