Pharmacokinetics of a new human plasma‐derived double virus inactivated and nanofiltered factor IX concentrate in previously treated severe or moderately severe haemophilia B patients (original) (raw)
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Haemophilia, 2009
Optimal replacement treatment in haemophilia B patients requires a good understanding of the pharmacokinetics of factor IX (FIX). The aim of this study was to compare the pharmacokinetic profile of Factor IX Grífols Ò , a highly purified human FIX concentrate with two specific pathogen inactivation/removal steps, to that of available FIX preparations. The study was an open, non-randomized trial including 25 male subjects older than 12 years of age with severe haemophilia B. Pharmacokinetic profile of the FIX preparation regularly used by the subjects was determined as control. Pharmacokinetic profile of Factor IX Grifols Ò was determined twice, one 7-15 days after control assessment and second after a 6 months period had elapsed. Results showed that all products had peak plasma levels of FIX:C within 30 min. Mean recovery was 1.3 ± 0.3 IU dL )1 per IU kg )1 for Factor IX Grifols Ò and 1.0 ± 0.3 IU dL )1 per IU kg )1 for control products (P < 0.001). The mean terminal half-life (t 1/2 ) for Factor IX Grifols Ò was 26.7 h and 26.8 h for control product. Pharmacokinetic parameters after 6 months of treatment with Factor IX Grifols Ò did not statistically differ from the parameters obtained with the first infusion. There were no adverse events related to Factor IX Grifols Ò for the duration of the study. In conclusion, Factor IX Grifols Ò has adequated pharmacokinetic properties comparable to the control plasma-derived FIX and these parameters remain stable after 6 months of treatment. Factor IX Grifols Ò can be an effective and safe plasma-derived FIX concentrate for replacement therapy in haemophilia B patients.
The Implication of New Developments in Hemophilia Treatment on Its Laboratory Evaluation
Cureus
Laboratories monitor hemophilia replacement therapy by specific coagulation factor measurement before and after the infusion of human-derived or recombinant factors. Bypassing agents are now used for patients with inhibitors. Recently, modified long-acting coagulation factors have been introduced, for which discrepant results may be expected when the measurement is performed with one-stage clotting or chromogenic assays. Currently, novel drugs not based on coagulation factors are being developed and further tested in clinical studies. These drugs do require new methods, and therefore, laboratory evaluation of hemophilia will undergo dramatic changes in the near future. Accordingly, present laboratory methods for monitoring, which include one-stage clotting or chromogenic assays, used to measure either factor VIII (FVIII) or factor IX (FIX), will not be sufficient. A thrombin generation test (TGT) or thromboelastometry may be used to monitor bypassing agents. For measuring modified long-acting coagulation factors, chromogenic assays will be probably more suitable than one-stage clotting assays. Novel drugs that are not based on coagulation factors, such as emicizumab, fitusiran, or concizumab, will require alternative methods.
Haemophilia, 2005
Therapeutic options for developing countries have to assure an optimum safety and efficacy and low-cost antihaemophilic concentrates. A single blind randomized crossover study was carried out in 12 previously treated HB patients, comparing the pharmacokinetics (PK), thrombogenicity (TG) and safety of two plasma-derived double-inactivated (solvent/detergent heating at 100°C, 30 min) factor IX (FIX) concentrates, UMAN COMPLEX DI (product A) [plasma-derived prothrombin concentrates (PCC)] and a high purity FIX concentrate AIMAFIX DI (product B, HPFIX). In a non-bleeding state, they received one single intravenous dose 50 IU FIX kg )1 of PCC or HPFIX, and after a wash-out period of 14 days, the other product. We evaluated acute tolerance and determined PK parameters based on FIX levels measured over a 50 h postinfusion period. We studied fibrinogen, platelets, antithrombin, F1 + 2, TAT, D-dimer, over a 360 min postinfusion period. Ten cases remained in on-demand treatment for 6 months, five with PCC and five with HPFIX. PK and anti-FIX inhibitors were repeated at 3 and 6 months. No inhibitors were detected. PK values (PCC vs. HPFIX): clearence (CL; mL h )1 kg )1 ) 5.2 ± 1.4 vs. 6.5 ± 1.4; the volume of distribution at steady state (mL kg )1 ) 154.9 ± 54.9 vs. 197.5 ± 72.5; mean residence time (h) 29.7 ± 8.1 vs. 30.7 ± 9.2; T 1/2 (h) 22.3 ± 7 vs. 23.5 ± 12.3; incremental recovery (IR; U dL )1 U )1 kg )1 ) 0.96 ± 0.17 vs. 0.76 ± 0.13. HPFIX showed significant lower IR and higher CL. There were no differences in PK at 3 and 6 months. In TG, significant increments in TAT and F1 + 2 at 30 min and 6 h were found with PCC. Product B PK results agrees with reported results for other HPFIX preparations. Use of PCC product A has to consider its thrombogenic activity.
Haemophilia, 2007
ReFacto is a recombinant B-domaindeleted, monoclonal antibody-purified, solvent-detergent-treated factor VIII (BDDrFVIII) with no albumin added to the final formulation. Although ReFacto has been shown to be bioequivalent to a plasma-derived FVIII product (Hemophil-M) in a randomized, crossover pharmacokinetic (PK) study, the comparability of ReFacto with the full-length (complete sequence) recombinant FVIII (FLrFVIII, Advate) product has not been previously examined in this manner. The primary objective of this study was to compare the PKs of ReFacto with those of Advate in patients with severe haemophilia A. This was a third-party unblinded, randomized, multicentre, two-period crossover PKs study of ReFacto and Advate in subjects with severe haemophilia A (FVIII:C £1%). Blood samples were collected over a 48-h period after i.v. administration of each of the FVIII products. FVIII:C was determined using the chromogenic substrate assay (CSA) in a central laboratory. The plasma FVIII:C PK parameters of ReFacto and Advate were determined using noncompartmental analysis. Bioequivalence was assessed on maximum plasma concentration (C max) and the area under the plasma concentration vs. time curves (AUCs) using an anova. The two products were judged to be equivalent if the 90% confidence limits of the ratio of the geometric mean values of C max and AUCs fell within the interval of 80-125%. Results from this PKs comparison of two different rFVIII products, using chromogenic substrate assay to measure FVIII:C, showed that ReFacto and Advate are bioequivalent to each other.
Haemophilia, 2011
Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine Ò , a high-purity human FIX concentrate. This open, single-arm, multicentre, non-randomized trial included 25 subjects (age ‡ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6-month follow-up. The degree of haemostasis control achieved was evaluated during a 12-month follow-up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL)1 per IU kg)1 at baseline and 1.23 ± 0.34 IU dL)1 per IU kg)1 6 months later. Terminal half-life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine Ò were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty-one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine Ò showed a pharmacokinetic profile in agreement with that of other plasma-derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B.