ReFacto®¹ and Advate®²: a single‐dose, randomized, two‐period crossover pharmacokinetics study in subjects with haemophilia A

Abstract

ReFacto is a recombinant B-domain-deleted, 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 < or =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 non-compartmental 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.

Retrospective analysis of differences in annual factor VIII utilization among haemophilia A patients

“…As expected, most of the rFVIII dispensed (89.1%) was administered to severe When not controlling for any other variables, severe patients treated on-demand utilized less FVIII than those on prophylaxis (median 1442 and 4060 IU kg )1 year )1 , respectively, P < 0.0001). After separating treatment regimen cohorts by age, there were significant differences in utilization between paediatric (<13 years old), adolescent (13)(14)(15)(16)(17)(18), and adult ( ‡19) patients receiving either episodic treatment or prophylaxis (Fig. 1, all P < 0.0001).…”

“…This reformulation of BDD-rFVIII was completed well before 2006 and would not interfere with the results. Although a pharmacokinetic crossover study [18] for the second generation BDD-rFVII product (ReFacto, Pfizer) showed BDD-rFVIII to be bioequivalent to a FL-rFVIII, half-life measurements were not provided. The follow-on BDD-rFVIII product (Xyntha in US, Refacto AF in EU, Pfizer) showed a 2-h difference in half-life between BDD-rFVIII and FL-rFVIII (11 h vs. 13 h, respectively) [19] although statistical significance was not provided.…”

Recombinant factor&nbsp;VIII in the management of hemophilia A: current use and future promise

“…Such direct comparison studies were performed using plasma-derived factor VIII (Hemophil M) and separately using full length recombinant factor VIII (Advate ® ; Baxter Healthcare). The direct pharmacokinetic comparisons showed that the factor VIII products are bioequivalent to each other 68,71…”

Products Used to Treat Hemophilia: Recombinant Products

“…Di Paola et al conducted a clinical study using BDD-rFVIII, rAFH-PMF, and pdFVIII to compare pharmacokinetic profiles using a chromogenic substrate assay for the measurement of FVIII:C. The results indicated that BDD-rFVIII and rAFH-PMF were equivalent [22].…”