Huan He (1), Libo Zhao (1), Meng Zhang (1), Ning Sun (1), Kun Huang (2), Zhenping Chen (2), Runhui Wu (2)
(1) Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China, (2) Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
Introduction: Hemophilia A is a X-linked inherited bleeding disorder which is characterized by a lack of coagulation factor VIII (FVIII)[1]. The FVIII replacement therapy with a recombinant coagulation factor VIII product was suggested for patients with hemophilia A. With the evolvement of hemophilia management in the past decades, prophylaxis was considered to be the main choice, especially for children[2]. The goal of prophylaxis is to maintain the FVIII level above a certain effective level in order to reduce bleeding. Dosage adjustment was determined by bodyweight (BW) in the past, but it ignored the considerable difference in pharmacokinetic (PK) profile of individuals which could lead to inadequate treatment[3]. Population pharmacokinetic (PopPK) model together with Bayesian approach has many applications, one important example of which is to estimate individual PK parameters which is used to find an optimal individual dose. However, no suitable Population pharmacokinetic model of FVIII has been developed in Chinese population, especially in Chinese children.
Objectives: The aims of the current study were 1) to develop a population pharmacokinetic model of FVIII in Chinese pediatric patients with hemophilia A, 2) to investigate its relationship with covariates such as body weight and Von Willebrand factor antigen (VWF:Ag) and 3) to provide dosing recommendations.
Methods: This pharmacokinetic study was conducted at a single center in China. Twenty-two pediatric patients with severe or moderate hemophilia A were enrolled. After a three-day washout period, patients were treated with FVIII and a reduced number of blood samples (pre-infusion and 1h, 9h, 24h, 48h post-infusion) were collected. One-stage assay was utilized to measure factor VIII levels of samples. A nonlinear mixed-effects modeling with the first-order conditional estimation-extended least squares (FOCE-ELS) method was used to build the population pharmacokinetic model by using Phoenix NLME software (version 8.1, Certara, St. Louis, MO). The impact of covariates including age, height, bodyweight (BW), VWF:Ag level, BMI and blood type on pharmacokinetic parameters was evaluated. Pediatric patients were divided into different subgroups in accordance with the included covariates. The final FVIII population pharmacokinetic model was used to simulate FVIII dosing strategies for pediatric patients in different subgroups.
Results: A total of 95 plasma concentrations from 22 pediatric patients (age ranged from 2.08 to 15 years old, BW ranged from 12.5 to 40.5 kg) with hemophilia A were used for developing the population pharmacokinetic model. A two-compartment model adequately described the FVIII concentration data which included structural parameters for volume of distribution (V), central clearance (CL), peripheral volume of distribution (V2), inter-compartmental clearance (Q) and baseline level of FVIII and is in accordance with published report[4]. Covariates BW and VWF:Ag level were identified and included in the final PopPK model. Typical value of V, CL, V2, Q, and baseline level of FVIII were 0.9 L (RSE = 9.28%), 0.089 L/h (RSE = 4.23%), 0.3 L (RSE = 12.33%), 0.073 L/h (RSE = 17.24%) and 9.97 IU/L (RSE = 20.51%) respectively [for child with BW of 22 kg, and VWF:Ag level of 83.95 IU/dL]. The central clearance is negatively correlated with VWF:Ag level. In the case of a high VWF level (170 IU/dL), CL would be reduced by around 40% compared with the population estimate of a typical baseline value (83.95 IU/dL) of VWF. A proportional error with a coefficient of variation of 11% (18.16%) provided the best description of the residual variability. Pediatric patients were divided into multiple groups according to BW and VWF:Ag level. Monte Carlo simulations were carried out to find the optimal dosing regimens for subgroups of pediatric patients with the precondition of over 95% trough concentrations exceeding 1 IU/dL. A dose regimen was recommended as 30 IU/kg Q48h for the children bodyweight under 17kg and VWF:Ag level between 65 and 85 IU/dL.
Conclusions: The population pharmacokinetic model for FVIII in Chinese pediatric patients with hemophilia A was successfully developed for the first time. Two significant covariates BW and VWF:Ag level were identified as key descriptors of the volume of distribution and clearance. This population model may be helpful for individualized FVIII administration in pediatric patients with hemophilia A.
References:
[1] Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. treatment guidelines working group on behalf of the World Federation of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013;19:e1–47.
[2] Gringeri A, Lundin B, von Mackensen S, et al. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011;9:700–10.
[3] Anthony LM, Rea CJ, Sorenson B. Inter- and intra-individual variation of factor VIII half-life in severe hemophilia A. Blood. 2010;116:544.
[4] Sven Björkman, Anna Folkesson, Siv Jönsson. Pharmacokinetics and dose requirements of factor VIII over the age range 3–74 years, Eur J Clin Pharmacol (2009) 65:989–998
Reference: PAGE () Abstr 9420 [www.page-meeting.org/?abstract=9420]
Poster: Drug/Disease Modelling - Paediatrics