Population Pharmacokinetic Analysis of Recombinant Fusion Protein Linking Coagulation Factor IX with Recombinant Albumin (rIX-FP) in Adult and Pediatric Patients with Severe Hemophilia B

Scientific Research Question: To characterize the population pharmacokinetics (PK) of rIX-FP in adult and pediatric patients, assess the covariates such as demographic and clinical factors that are potential determinants of rIX-FP PK variability, simulate FIX activity-time profiles for different dosing regimens, and assess the feasibility of extended dosing regimens of 100 IU/kg every 21 days for adults and 75 IU/kg every 14 days for pediatric patients.

Methodology: A total of 116 hemophilia B patients (FIX ≤2%), aged 1 to 70 years, were included. Patient blood samples were collected and FIX activity determined using the one-stage clotting assay. A population PK model was developed in NONMEM 7 software, where goodness-of-fit and prediction-corrected visual predictive check (pcVPC) were used for model evaluation. Exogenous FIX activity levels were simulated for various dosing scenarios.

Findings: FIX activity levels were well-described using a 2-compartment population PK model. The parameters were estimated with reasonable precision (relative standard error < 26%) and the final model was supported by the goodness-of-fit diagnostics and pcVPC. Median exogenous (rIX-FP) simulated trough FIX activity is approximately 5% in patients ≥12 years receiving 100 IU/kg every 21 days, and is approximately 5% for pediatric patients (6 to < 12 years) and 3% for ages < 6 years with both pediatric age groups receiving 75 IU/kg every 14 days.

Conclusions: rIX-FP PK was well characterized using a population PK model approach. Dosing of rIX-FP can be evaluated by using this model to simulate FIX activity-time profiles for different dosing schedules. The population PK simulations suggest that the majority of adult and pediatric Hemophilia B patients receiving rIX-FP on 21-day and 14-day extended interval dosing regimens, respectively, reach sufficient FIX activity levels to transition from severe to a mild or moderate hemophilia classification.

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