Confirmation of longer FIX activity half-life with prolonged sample collection after single doses of nonacog alfa in patients with haemophilia BFinancial support: This study was sponsored by Pfizer Inc. Editorial support was provided by Teri O’Neill of Peloton Advantage and was funded by Pfizer Inc. No author received an honorarium related to the development of this manuscript.
07. Oktober 2016
Accepted after major revision: 01. März 2017
07. November 2017 (online)
A multicentre, single–dose study enrolled 12 previously treated patients with moderately severe to severe (factor IX [FIX] levels ≤2 IU/dl) haemophilia B to assess FIX pharmacokinetics after nonacog alfa administration and to evaluate the impact of length of sampling time on half-life (t½). After refraining from FIX replacement for four days, patients received 50 IU/kg as an intravenous (IV) infusion over 10 minutes. Blood samples were collected predose and 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72, and 96 h post dose. Tolerability and safety were assessed by monitoring adverse events and were subsequently summary tabulated. FIX activity was measured by a one-stage clotting assay with a lower limit of quantification of 0.010 IU/ml, and inhibitors to FIX were measured using the Bethesda assay. Pharmacokinetic parameters were calculated by noncompartmental analysis and were descriptively summarised. Half-life estimates were calculated first using all available data, then excluding 96-h observations (truncated at 72 h) and, finally, excluding both 72– and 96-h observations (truncated at 50 h). No patient was positive for FIX inhibitors. No treatment-emergent adverse events were reported. Prolonging the duration of the sample collection to 96 h resulted in a terminal t½ estimate of 39.6 ±7.4 h in the eight patients aged 18 years and older, which was longer than the estimates obtained using shorter periods of observation: 29.6 ± 5.5 h (truncated at 72 h) and 27.2 ± 7.0 h (truncated at 50 h). To accurately assess an adult patient’s t½, sampling should be continued for at least 96 h.
- 1 Roth DA, Kessler CM, Pasi J. et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrations. Blood 2001; 98: 3600-3606.
- 2 Ragni MV, Pasi KJ, White GC. et al. Use of recombinant factor IX in subjects with haemophilia B undergoing surgery. Haemophilia 2002; 8: 91-97.
- 3 Korth-Bradley JM, Rendo P, Smith L. et al. Pharmacokinetics, efficacy, and safety of nonacog alfa in previously treated patients with moderately severe to severe hemophilia B. Clin Ther 2016; 38: 936-944.
- 4 Lambert T, Recht M, Valentino LA. et al. Reformulated BeneFIX: efficacy and safety in previously treated patients with moderately severe to severe haemophilia B. Haemophilia 2007; 13: 233-243.
- 5 Shapiro AD, Paola J, Cohen A. et al. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B. Blood 2005; 105: 518-525.
- 6 Monahan PE, Liesner R, Sullivan ST. et al. Safety and efficacy of investigator-prescribed BeneFIX prophylaxis in children less than 6 years of age with severe haemophilia B. Haemophilia 2010; 16: 460-468.
- 7 Suzuki A, Tomono Y, Korth-Bradley JM. Population pharmacokinetic modeling of factor IX activity after administration of recombinant factor IX in patients with haemophilia B. Haemophilia 2016; 22: e359-366.
- 8 Powell JS, Pasi KJ, Ragni MV. et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med 2013; 369: 2313-2323.
- 9 Guideline on clinical investigation of recombinant and human plasma-derived factor IX products, 21 July 2011, EMA/CHMP/BPWP/144552/2009 Committee for medicinal products for human use (CHMP), effective date: February 1, 2012.
- 10 Chang H-H, Yang Y-L, Hung M-H. et al. Pharmacokinetic study of recombinant human factor IX in previously treated patients with hemophilia B in Taiwan. J Formos Med Assoc 2007; 106: 281-287.
- 11 Valentino LA, Rusen L, Elezovic I. et al. Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects. Haemophilia 2014; 20: 398-406.
- 12 Kavakli K, Smith L, Kuliczkowski K. et al. Once-weekly prophylactic treatment vs on-demand treatment with nonacog alfa in patients with moderately severe to severe haemophilia B. Haemophilia 2016; 22: 381-388.
- 13 Morfini M, Dragani A, Paladino E. et al. Correlation between FIX genotype and pharmacokinetics of nonacog alpha according to a multicentre Italian study. Haemophilia 2016; 22: 537-542.
- 14 Bjorkman S. Population pharmacokinetics of recombinant factor IX: implications for dose tailoring. Haemophilia 2013; 19: 753-757.
- 15 Feng D, Stafford KA, Broze GJ, Stafford DW. Evidence of clinically significant extravascular stores of factor IX. J Thromb Haemost 2013; 11: 2176-2178.