ABSTRACT
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.
Subject(s)
Factor VIII/administration & dosage , Factor VIII/pharmacokinetics , Hemophilia A/prevention & control , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacokinetics , Adolescent , Adult , Age Factors , Aged , Body Weight , Child , Child, Preschool , Dose-Response Relationship, Drug , Female , Hemophilia A/blood , Hemophilia A/epidemiology , Humans , Infant , Male , Middle Aged , Models, Theoretical , Prognosis , Retrospective Studies , Tissue Distribution , United States/epidemiology , Young AdultABSTRACT
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 < or = 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.
Subject(s)
Factor VIII/therapeutic use , Hemophilia A/therapy , Adolescent , Adult , Aged , Child , Child, Preschool , Hemophilia A/immunology , Hemorrhage/prevention & control , Humans , Infant , Maximum Tolerated Dose , Middle Aged , Patient Compliance , Prospective Studies , Safety , Serum Albumin/deficiency , Treatment Outcome , Young AdultABSTRACT
Evaluation of factor F(V)III replacement in patients with haemophilia A undergoing surgery is critical for FVIII concentrates, yet large scale, multi-center prospective studies, particularly using continuous infusion, are generally lacking for new products. This study evaluated efficacy and safety of a newly developed recombinant FVIII (rAHF-PFM) administered by bolus or continuous infusion in haemophilia A patients undergoing surgery. Subjects > or =5 years of age with baseline FVIII:C < or =2%, and > or =150 prior FVIII exposure days were included in this prospective, international, open-label, uncontrolled clinical trial. rAHF-PFM was administered perioperatively by bolus infusion (BI) or continuous infusion (CI) according to the standard use at the center to prevent bleeding complication. Both the surgeon and haematologist rated efficacy during hospitalization. Fifty-eight subjects underwent 65 surgical procedures (22 major haemorrhagic risk; 35 minor, 8 dental procedures). Bolus infusion was used exclusively in 47 procedures and continuous infusion, with or without supplemental bolus infusions, in 18. Haemostatic efficacy was assessed as excellent or good for 100% of intraoperative ratings (17 CI, 44 BI, 61 total procedures), and 100% of postoperative ratings performed at time of discharge (18 CI, 44 BI, 62 total procedures). Median total consumption of rAHF-PFM during hospitalization was 822 IU/kg/surgery with CI and 910 IU/kg/surgery with BI. Overall rAHF-PFM was well tolerated, and FVIII inhibitors were not detected. In conclusion, rAHF-PFM administered via continuous infusion or bolus injections is safe, non-immunogenic, and effective for perioperative hemostatic management in previously treated haemophilia A patients.
