Page 283 - Haematologica May 2020

Coagulation & its Disorders
Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients
Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1443-1453
João A. Abrantes,1 Alexander Solms,2 Dirk Garmann,3 Elisabet I. Nielsen,1 Siv Jönsson1 and Mats O. Karlsson1
1Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; 2Bayer, Berlin, Germany and 3Bayer, Wuppertal, Germany
ABSTRACT
Pharmacokinetic-based prophylaxis of replacement factor VIII (FVIII) products has been encouraged in recent years, but the relationship between exposure (factor VIII activity) and response (bleeding fre- quency) remains unclear. The aim of this study was to characterize the rela- tionship between FVIII dose, plasma FVIII activity, and bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled phar- macokinetic and bleeding data during prophylactic treatment with BAY 81- 8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of FVIII activity and longitudinal bleeding fre- quency, as well as bleeding severity, were described using non-linear mixed effects modeling in NONMEM. In total, 183 patients [median age 22 years (range, 1-61); weight 60 kg (11-124)] contributed with 1,535 plasma FVIII activity observations, 633 bleeds and 11 patient/study characteristics [medi- an observation period 12 months (3.1-13.1)]. A parametric repeated time-to- categorical bleed model, guided by plasma FVIII activity from a 2-compart- ment population pharmacokinetic model, described the time to the occur- rence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability in the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research was based on a post-hoc analysis of the LEOPOLD stud- ies registered at clinicaltrials.gov identifiers: 01029340, 01233258 and 01311648.
Introduction
Hemophilia A is an X-linked hereditary bleeding disorder caused by the defi- ciency of coagulation factor VIII (FVIII). The severity of the disease is inversely correlated with the amount of factor that an individual is able to produce, and nearly half of the cases correspond to the severe laboratory phenotype (endoge- nous plasma FVIII activity levels <1 IU/dL).1,2 Prophylaxis with FVIII concentrates is currently considered the treatment of choice to decrease the frequency of bleed- ing and preserve musculoskeletal function.3-5 The population pharmacokinetics (PK) of FVIII products has been extensively studied, and it has been seen that the elimination half-life varies substantially between patients.6,7 Thus, the individual disposition of FVIII cannot be adequately predicted by average PK parameters and demographic characteristics, and PK-based dosing has been encouraged to opti- mize dosing regimens in the prophylactic setting.8-10 In brief, PK-based dosing relies on Bayesian estimation to estimate the individual PK parameters by combin- ing patient information (dose, FVIII activity measurements and demographic char- acteristics, e.g. age, body weight) with information previously collected from a patient population by means of a population PK model.11,12 Based on the estimated
Correspondence:
MATS O. KARLSSON
mats.karlsson@farmbio.uu.se
Received: February 1, 2019. Accepted: July 23, 2019. Pre-published: August 1, 2019.
doi:10.3324/haematol.2019.217133
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1443
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