Characterization of the Pharmacokinetics of rFVIII in Young Pre-School Children with Hemophilia, Including an Analysis of the Influence of Age and Body Weight.
Bibliographic record
Abstract
Abstract 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 < 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 < 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 < 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 < 6 y old.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".