New Approach in Assessing the Pharmacokinetic/Pharmacodynamic Relationship in Patients with Severe Hemophilia A Using Data from BAY 81-8973 Studies

Background: The relationship between factor VIII (FVIII) level or time spent below a certain FVIII level and bleeding rate has previously been analyzed using different regression analysis methods (Collins PW, et al. J Thromb Haemost. 2009;7[3]:413-420; Ahnström J, et al. Haemophilia. 2004;10[6]:689-697; den Uijl IE, et al. Haemophilia. 2011;17[1]:41-44). Although a relationship could be generally confirmed, results were not fully consistent. Nevertheless pharmacokinetic (PK)-guided dosing that targets a certain trough FVIII level, usually 1 IU/dL, is used in clinical practice.

Objectives: To establish a PK/pharmacodynamic (PD) relationship between FVIII replacement and the occurrence of repeated bleeds and to investigate the effect of PK-guided dosing by simulations

Patients/methods: Data from 121 patients aged 12-61 years with severe hemophilia A (FVIII <1 IU/dL) who were treated prophylactically with a new full-length recombinant FVIII (BAY 81-8973) and who had PK information available were included in the analysis. The PK/PD relationship was analyzed with a repeated time-to-event method, using nonlinear mixed-effect modeling.

Results: A relationship between FVIII concentrations over time and bleeding hazard could be identified. In addition, a time-dependent effect was significant in the analysis, resulting in a decrease in bleeding risk when patients were treated prophylactically with BAY 81-8973. Documented bleeds in the year before the study gave insight into the different bleeding risks of patients. Simulation results show that a fixed dose of FVIII on a study level might be as effective as PK-guided dosing.

Conclusion: The patient's documented bleeding history (phenotype) should be considered when dosing decisions for replacement therapy are being made.