Pharmacokinetics, Coagulation Factor Consumption, and Product Efficacy in Patients Crossing Over from Full-Length FVIII to B-Domain Deleted R-FVIII and Back to Full-Length FVIII.

Introduction: Treatment with B-domain deleted recombinant factor VIII (BDD-rFVIII) has proven to be effective and safe both in clinical trials and post marketing surveillance studies. However, intermittent concerns have been raised regarding the pharmacokinetic performance, efficacy and incidence of inhibitor formation with the BDD-rFVIII product.

Aims: The objective of the present study was to perform a retrospective survey of half-life measurements, clinical efficacy and safety in patients with severe Haemophilia A, when switching treatment from full-length FVIII (FL-FVIII) to BDD- rFVIII and then back to full-length FVIII. We hypothesized that the biological half-life of FVIII would be equal regardless of the product used. Furthermore, we hypothesized that the total factor consumption and bleeding frequency would be indistinguishable irrespective of product used. Finally, we report on safety as evaluated by development of inhibitors and clinical outcome following surgery.

Methods: Patients treated with BDD-rFVIII (between 1998 and 2008) were identified from an in-house database. Data collected included annual half-life (T/2) and recovery times (K values), total coagulation factor consumption, and number of bleeds per year as measures of clinical efficacy. Safety data consisted of surgical outcome data and incidence of inhibitor formation. The information was extracted from electronic databases and verified by a review of patients’ clinical notes. The outcome data was non-parametric, hence, paired analysis was performed using Wilcoxon signed rank test and Friedman ANOVA. Data is given as a median value and range. P-value < 0.05 was set as level of statistical significance.

Results: In total, 70 patients received BDD-rFVIII on at least one occasion. Following a specified list of criteria, evaluable data was obtainable for 15 males, all with verified severe Haemophilia A (FVIII:C <1%). The average age was 10.2 years (median 10, range 4–17). The median duration on BDD-rFVIII was 30 months (range 20–54). Using the one-way non-parametric ANOVA, no statistically significant difference was detected between the half-life and recovery times recorded during the switch from FL-FVIII (T/2 median 9.15 hours, range 6.4–22; K median 2.7, range 2.0–3.4) to BDD-rFVIII (T/2 median 9.7, range 4.7–16.8; K median 1.8, range 1.0–3.5) and back to FL-FVIII (T/2 median 9.0, range 5.0–19.5; K median 2.0, range 1.6–2.8). Furthermore, there was no significant difference in coagulation factor usage (BDD-rFVIII median 4803 iu/kg/year, range 659–11304; FL-FVIII median 5349, range 1691–10146), nor number of reported bleeds (BDDrFVIII median 6, range 0–24; FL-FVIII median 5.0, range 0–17). None of the 15 patients developed an inhibitor on BDD-rFVIII. Of the total 70 patients, 11 received BDD-rFVIII to cover surgical procedures (8 minor, 3 major interventions). There were no reports of excess bleeding.

Conclusions: In this retrospective survey, BDD-rFVIII was found to be equivalent to other FVIII products in terms of half-life measurements, clinical efficacy and safety.