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?

pharmaceutics Article 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? Quentin Allard 1 , Zoubir Djerada 1 , Claire Pouplard 2 , Yohann Repessé 3 , Dominique Desprez 4 , Hubert Galinat 5 , Birgit Frotscher 6 , Claire Berger 7 , Annie Harroche 8 , Anne Ryman 9 , Claire Flaujac 10 , Pierre Chamouni 11 , Benoît Guillet 12 , Fabienne Volot 13 , Jean Szymezak 14 , Philippe Nguyen 14 and Yoann Cazaubon 1, * 1 2 3 4 5 6 7 8 9 10 11 12 13 14 * Department of Medical Pharmacology, University Hospital of Reims, EA3801, SFR Cap-Santé, University of Reims, 51100 Reims, France; (Q.A.); (Z.D.) Department of Haemostasis, University Hospital of Tours, 37000 Tours, France; Department of Haemostasis, University Hospital of Caen, 14000 Caen, France; Department of Haemostasis, University Hospital of Strasbourg, 67000 Strasbourg, France; Department of Haemostasis, University Hospital of Brest, 29200 Brest, France; Department of Haemostasis, University Hospital of Nancy, 54000 Nancy, France; Department of Haemostasis, University Hospital of Saint-Etienne, 42000 Saint-Etienne, France; Department of Haemostasis, Hospital Necker, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Department of Haemostasis, University Hospital of Bordeaux, 33000 Bordeaux, France; Department of Haemostasis, Hospital of Versailles, 78000 Versailles, France; Department of Haemostasis, University Hospital of Rouen, 76000 Rouen, France; Department of Haemostasis, University Hospital of Rennes, 35000 Rennes, France; Department of Haemostasis, University Hospital of Dijon, 21000 Dijon, France; Department of Haemostasis, University Hospital of Reims, EA3801, SFR Cap-Santé, University of Reims, 51100 Reims, France; (J.S.); (P.N.) Correspondence: ; Tel.: +33-3-26-83-75-31; Fax: +33-3-26-78-84-56 Received: 23 February 2020; Accepted: 17 April 2020; Published: 21 April 2020



 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. Pharmaceutics 2020, 12, 380; doi:10.3390/pharmaceutics12040380 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, 380 2 of 13 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. Keywords: factor VIII; severe haemophilia A; pharmacokinetics; switch; modelling; dose tailoring 1. Introduction Haemophilia A is a genetic coagulation pathology. It is manifested by bleeding, secondary to the deficit of one of the factors of coagulation: factor VIII (FVIII). The treatment of haemophilia A is based on supplementation, prophylactic, or on-demand, in FVIII. Since the development of these treatments in the 1950s, the quality of life and life expectancy of haemophilia A patients improved and they are tending, in developed countries, to approach those of the non-affected population [1,2]. Currently, there is no optimal prophylactic regimen for all patients. Despite an adaptation of dose according to weight, the high interindividual variability (IIV) of FVIII pharmacokinetics (PK) makes it difficult to retain the coagulating activity of FVIII (FVIII: C) above a targeted level [3]. It is essential to improve patient safety while optimising the use of FVIII [4]. An under-dose of FVIII exposes the patient to a risk of bleeding, whereas overdose leads to the excessive use of resources without therapeutic benefit [5,6]. Ideally, the patient’s PK profile is taken into account and is scheduled in advance to develop an optimised dosing regimen [7]. The main obstacles to this approach in current clinical practice are the complex calculations that are involved and a large number of samples required during the first 72 h [8,9]. This last problem can be overcome by using the pharmacokinetic of population (PKPOP) approach, reducing the number of samples required for a precise estimation of the PK parameters [3]. PKPOP approach allows for quantifying the interindividual variability of the estimated PK parameters. Knowing the particularities linked to FVIII makes it possible to explain part of the variability by testing the covariates having a biological meaning (e.g., age, weight, von Willebrand Factor, ABO blood group). Once qualified, the model becomes able to determine the PK parameters of the individual and, thus, personalise the dose administered according to the frequency of administration, individual covariates, and desired target reassessed based on patient’s life context. Thus, the optimised prophylactic regimen for each patient that allows for maintaining FVIII:C above its targeted threshold can be more effectively determined [10]. The objectives of this study were to develop a global population PK model in patients with severe haemophilia A and compare half-life (HL) between patients switching from standard half-life (SHL) to extended half-life (EHL). 2. Materials and Methods 2.1. Study Design, Subjects, Sample Collection and Assay Method This retrospective multicentre (n = 13) study was a characterisation of interindividual PK variability of data collected between 2012 and 2019 from patients treated with FVIII concentrates for mainly severe haemophilia A. The data were taken from current practice. An individual information note was distributed to patients to ensure that they were not opposed to participating in this study. Thus, the database is in compliance with the reference methodology MR004 of the “Commission Nationale de l’Informatique et des Libertés”. All of the patients had severe, moderate, or minor haemophilia A and did not present inhibitors during PK analysis. FVIII:C was measured using the one-stage clotting assay principle. For FVIII:C measurement, the couple, (...truncated)