Advancing personalized care in hemophilia A: ten years' experience with an advanced category antihemophilic factor prepared using a plasma/albumin-free method.

Detailed analysis of data from studies of recombinant antihemophilic factor produced using a plasma/albumin-free method (rAHF-PFM) in previously treated patients showed a substantial level of interpatient variation in pharmacokinetics (PKs), factor VIII dosing, and annualized bleed rate (ABR), suggesting that individual patient characteristics contributed to outcome. For example, plasma half-life (t1/2), recovery, and clearance appeared to differ between patients aged <6 years and 10-65 years. Prophylaxis resulted in lower ABRs than episodic treatment in both age groups; better adherence to the prophylactic regimen resulted in a lower ABR in patients aged 10-65 years. The weekly frequency of dosing and adherence to dosing were both significantly and inversely related to the rate of bleeding (young children, P<0.0001 for both all bleeds and joint bleeds; older patients, P<0.0001 for all bleeds and P<0.05 for joint bleeds), as was adherence to dosing frequency (P<0.0001 for all comparisons). A post-marketing randomized study of prophylaxis demonstrated that a PK-guided dosing regimen, based on an individual patient's rAHF-PFM PK (infusion interval, estimated t1/2, and recovery), was as effective as standard prophylaxis and that both prophylactic regimens were superior to episodic treatment with respect to ABR and quality of life measures. Thus, compared with standard prophylaxis, the PK-guided regimen achieved comparable efficacy with fewer weekly infusions. A two-compartment population PK model describes the PK data across the entire age range and forms the basis for future PK-guided therapy with rAHF-PFM. The model confirmed a shorter t1/2 and faster clearance of rAHF-PFM in children <6 years of age versus patients ≥10 years and predicted similar PK parameters with either a full or reduced blood sampling schedule, offering the potential for the use of PK-guided, individualized treatment in the routine clinical care setting

The relative burden of haemophilia A and the impact of target joint development on health-related quality of life: results from the ADVATE Post-Authorization Safety Surveillance (PASS) study.

Studies with haemophilia A (HA) patients have shown burden in health-related quality of life (HRQOL) when compared with general population norms. In the current study, HA patients' SF-36v2 health survey scores were compared with general population norms and to patients with other chronic conditions. The impact of target joints (TJs) on HRQOL was also examined. The sample was a subset of HA patients enrolled in the Post-Authorization Safety Surveillance (PASS) programme: a prospective open-label study in which ADVATE [Antihaemophilic Factor (Recombinant), Plasma/Albumin-Free Method] was prescribed. A total of 205 patients who were ≥ 18 years old and had SF-36v2 baseline scores were selected for this study. To measure the burden of HA on HRQOL, manova analyses compared these SF-36v2 scores to age- and gender-matched general population US and EU norms and to patients from other chronic condition groups. manova and correlational analyses examined the relations among TJ, age and SF-36v2 scores. Comparisons with general population norms confirm that HA negatively impacts physical, but not mental, HRQOL. Comparison with other chronic conditions shows the physical burden of HA is greater than for chronic back pain but similar to diabetes and rheumatoid arthritis, while the mental burden of HA is less than for all three patient groups. The presence of TJs was negatively associated with physical HRQOL, although this association was much larger for older patients (45+ years) than for younger ones. Physical, but not mental, HRQOL is diminished in HA patients. Target joints are associated with lower physical HRQOL, although this effect is moderated by age

Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A

Background: Hemophilia A is an X-linked bleeding disorder that results from insufficient levels of factor VIII (FVIII) coagulant activity. Objective: To evaluate the efficacy and safety of ADVATE® rAHF–PFM (Baxter Healthcare Corporation), a recombinant FVIII concentrate manufactured without human or bovine blood-derived additives, and to assess the effect of compliance with prophylactic use in preventing bleeding episodes (BEs). Methods: Clinical data were integrated from six prospective studies. Two hundred thirty-four hemophilia A subjects (FVIII levels ≤ 2%) (median age 14.7 (range: 0.02 – 72.7) years) were included. Results: BEs were managed with one or two infusions and nearly all (1953/1956) responded to treatment. Compliance with a prophylactic treatment regimen significantly reduced the incidence of BEs (p = 0.0061) and prevented non-traumatic joint BEs (median annualized BE rate was 0). One previously treated subject developed an inhibitor; no other safety concerns were observed. Conclusions: These results reinforce the efficacy and safety of rAHF-PFM and suggest that compliance is an essential contributor to the effectiveness of prophylaxis in the treatment of hemophilia A

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study

Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate-one virally inactivated with solvent detergent, the other with an additional heat-treatment step--were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction

Population pharmacokinetics of recombinant factor VIII: The relationships of pharmacokinetics to age and body weight

Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling

Factor IX inhibitors and anaphylaxis in hemophilia B

Purpose: We present clinical and laboratory data on 18 children from 12 hemophilia treatment centers in the United States, Canada, and Europe with the purpose of disseminating information regarding a recently recognized, potentially life-threatening complication of treatment in very young children with hemophilia B. Patients and Methods: Twelve hemophilia centers from the United States, Canada, and Europe provided clinical information and laboratory data concerning 18 children who had severe allergic reactions to infused factor (F) IX in close association with the development of an inhibitor to FIX. Laboratory testing for establishment of the diagnosis of hemophilia B and inhibitor to FIX was done locally at the centers treating these patients. FIX gene analysis was performed at one of six molecular genetics institutes. Results: All 18 children had severe hemophilia B, and in each an inhibitor antibody to FIX developed. The median age at the time of anaphylaxis (or anaphylactoid reaction) was 16 months, and the median number of exposure days to FIX was 11. The FIX inhibitor was detected almost simultaneously with the first occurrence of anaphylaxis in 12 of 18 patients. Maximum inhibitor liters were 4.5-600 Bethesda units (BU), with a median titer of 48 BU. FIX gene analysis, performed in 17 of 18 patients, demonstrated complete deletion of the FIX gene in 10 and major derangements in seven. Immune tolerance induction (ITI) regimens have been attempted in 12 patients, with generally poor responses. Two of the 12 experienced nephrotic syndrome while on ITI. Recombinant FVIIa has been successfully used to treat bleeding episodes in 11 of these children. Conclusion: Physicians treating young children with hemophilia B should be aware of the potentially life- threatening complication of anaphylaxis. Children with complete gene deletions or major derangements of the FIX gene appear to be at greater risk. Those identified by genotype as being at greater risk may need to receive their first 10-20 treatments in a medical facility equipped for handling such emergencies. Recombinant FVIIa, although not licensed for use in the United States, appears to be the most suitable treatment option for bleeding episodes in such patients