Characterization of the Pharmacokinetics of rFVIII in Young Pre-School Children with Hemophilia, Including an Analysis of the Influence of Age and Body Weight.
Authors: Blanchette Victor , Shapiro Amy D. , Liesner Raina , Hernandez Fernando , Retzios Anastassios D. , Schroth Phillip , Fritsch Sandor , Spotts Gerald , Ewenstein Bruce M. 
Published: April 2020

Commencement of prophylaxis at an early age for management of severe hemophilia A is widely recommended in order to prevent or minimize disabling arthropathy. Knowledge of the pharmacokinetics of replacement clotting factors is key to achieving optimal dosing regimens. However, the majority of pharmacokinetic studies on replacement FVIII have been conducted in older children and adults, and evidence on the pharmacokinetics of FVIII in pre-school children is primarily anecdotal. This study is the first to evaluate the pharmacokinetics of rFVIII in a large cohort of children &lt; 6 y of age. The evaluation was part of an open-label, multicenter study of 53 subjects with FVIII ≤ 2% and ≥ 50 prior FVIII exposure days. The mean age of the cohort was 3.1 ± 1.5 y (range, 1.1–6.0 y). Standard pharmacokinetic parameters were assessed in accordance with the guidelines for pediatric patients of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. A single dose was infused of 50 IU/kg of a recently-developed recombinant FVIII product, ADVATE rAHF-PFM, a full-length FVIII concentrate prepared without the addition of human or animal plasma proteins. In an intent-to-treat analysis of results from 52 subjects, mean plasma half-life (t1/2) was 9.7 ± 1.9 h, the adjusted in vivo recovery (IVR) was 1.9 ± 0.4 IU/dL/IU/kg, and clearance was 0.04 ± 0.01 dL/kg•h. These data contrast with those of a recent study of rAHF-PFM in individuals with a median age of 18 (range, 10–65) in which the t1/2 was 12.0 ± 4.3 y and IVR was 2.4 ± 0.5 (Tarantino et al, Haemophilia, 2004, in press). No previous studies have examined whether pharmacokinetic changes in t1/2 and IVR related to age or weight occur in young pediatric patients. There was no significant correlation between IVR and age (r = −0.09, p = 0.54); however, there was a moderate correlation between IVR and body mass index (BMI) (r =.049; p &lt; 0.001). There was also a weak correlation between t1/2 and age (r =0.34; p = 0.02). A significant inverse correlation was found between IVR and volume of distribution at steady state (Vss) (r = −0.82, p &lt; 0.001). Subsequent assessment of the safety, efficacy and immunogenicity of rAHF-PFM is ongoing in these patients. In an interim analysis, after a total of 3,698 infusions, no inhibitors or other adverse events related to rAHF-PFM have been reported (median exposure days = 74). Of 210 bleeding episodes, 92.4% required ≤ 2 infusions. Median numbers of annual total bleeding episodes (joint + non-joint) for patients on either standard (n = 17) or modified (n = 25) prophylaxis or on-demand treatment (n = 4) were 2.85, 2.31, and 20.07, respectively. This study demonstrates for the first time in pre-school children and toddlers detectable correlations in the pharmacokinetics of rFVIII between age and t1/2, and between IVR and BMI, and that ADVATE rAHF-PFM is efficacious, well-tolerated and non-immunogenic in young children. Further research is required to define factors affecting inter-individual variation in t1/2 of rFVIII and the accelerated pharmacokinetics in children &lt; 6 y old.