Population pharmacokinetics of recombinant coagulation factor VIII‐SingleChain in patients with severe hemophilia A

• Published in: Journal of thrombosis and haemostasis 2017-06, Vol.15 (6), p.1106-1114
• Main Authors: Zhang, Y., Roberts, J., Tortorici, M., Veldman, A., St Ledger, K., Feussner, A., Sidhu, J.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Blood Coagulation Tests; Child; Child, Preschool; Computer Simulation; Cross-Over Studies; Drug Administration Schedule; Factor VIII - pharmacokinetics; factor VIII; Hemophilia A - blood; Hemophilia A - drug therapy; hemophilia A; Humans; Male; Middle Aged; Models, Biological; pharmacokinetics; recombinant proteins; Recombinant Proteins - pharmacokinetics
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.13662

Essentials rVIII‐SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity–time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII‐SingleChain with intervals of up to twice per week. Summary Background Single‐chain recombinant coagulation factor VIII (rVIII‐SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII‐SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII‐SingleChain PK; and (iii) simulate various dosing scenarios of rVIII‐SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12–65 years; n = 39 for  85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL−1, at all times with three‐times‐weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg−1) and highest (50 IU kg−1) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg−1 rVIII‐SingleChain, 62–80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL−1 at day 7. Conclusions The population PK model adequately characterized rVIII‐SingleChain PK, and the model can be utilized to simulate FVIII activity–time profiles for various dosing scenarios.