Novel and Clinically Significant Factors Influencing the Pharmacokinetic Variability of Recombinant Factor VIII (Kogenate-FS) in Children.
Bibliographic record
Abstract
Abstract Understanding the pharmacokinetics of factor VIII (FVIII) is critical to maximise the clinical benefit of clotting factor replacement therapy. Little is known about the pharmacokinetics of recombinant FVIII (rFVIII) in children and current dosing regimes, largely based on adult pharmacokinetic data, may be inappropriate. Further, there is limited information about factors determing the pharmacokinetic variability of FVIII between children. We performed a pharmacokinetic study in 20 children with severe haemophilia A (mean age 12.8 years) following a bolus of 50 U/kg of rFVIII (Kogenate-FS, Bayer Health Care). FVIII:C levels were assessed at 10 time points to determine the effect of patient size, age and pre infusion vWF:Ag level on FVIII pharmacokinetics. The patients had no history of inhibitors to FVIII (>0.5 BU). The mean incremental FVIII recovery was 1.87 (U/ml)/(U/kg) (range 1.25– 2.76) which is significantly lower than adult pharmacokinetic studies. (Table 1) FVIII recovery showed a greater correlation with body surface area (BSA, Spearman correlation p = 0.037) than to weight (p = 0.048) suggesting dosing based on BSA may lead to more predictable FVIII recovery in children. The mean half-life of FVIII was 10.7 hours (range 7.8 to 15.3) and is reduced in comparison to adult studies. FVIII half-life showed a positive correlation with levels of vWF:Ag (p = 0.0001) (Figure 1) and half life was reduced in six patients with FVIII inhibitor titres between 0.05–0.15 Nijmegen modified BU (p = 0.06). The correlation of rFVIII half-life with vWF:Ag levels may provide a basis for pharmacological augmentation of vWF:Ag levels to prolong rFVIII half life and may be of major benefit in countries with a limited supply rFVIII. The finding that FVIII half-life is reduced in patients with inhibitor titres that have previously been regarded as clinically insignificant suggests that standards and methodologies for the measurement of inhibitors should be re-evaluated. This study shows that the pharmacokinetics of rFVIII in children are unique and that BSA, pre infusion levels of vWF and the presence of low, previously considered non-clinically significant inhibitors may affect the pharmacokinetics of Kogenate-FS in children. These relationships, and the potential to improve dosing schedules for FVIII in children, need further study. Comparison of results from our centre with other published pharmacokinetic studies of rFVIII. Reference Number of patients Mean age (range) (Years) Mean incremental recovery (U/ml)/(U/kg) Mean half life (hours) Mean clearance (ml/hr/kg) Mean volume of distribution steady state (ml/kg) ¥ Results represent pooled data of one rFVIII product prepared at two different sites assessed by one stage assay. Only week 1 of serial pharmacokinetic studies is presented. Barnes (2004) 20 12.8 (4.4 – 18.1) 1.9 10.7 4.1 59.2 Lee (1999)¥ 30 N/A 2.5 12.7 2.0 62.6 Fijnvandraat (1997) 12 34.0 (17 – 64) 2.4 11.3 3.2 44.8 Harrison (1991) 14 34.1 (23 – 72) 2.8 16.5 2.4 51.2 Schwartz (1990) 17 N/A 2.7 15.8 2.5 50.5 Figure Figure
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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 | 0.001 | 0.004 |
| 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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".