Half-Life of Nonacog Alfa Revised in Patients with Hemophilia B

Brigitte Tardy, MD

A recent investigation into the function of nonacog alfa prophylaxis in patients with hemophilia suggested that the terminal half-life (THL) of the recombinant factor IX (FIX) was longer than previously assumed in both younger and older patients.

Previous research had established safety and efficacy for recombinant FIX nonacog alfa in patients with hemophilia B for the control and prevention of bleeding events in adults with children.

However, its half-life was determined in clinical studies that involved limited sampling (72 h) and was considered short.

As such, and investigative team led by Brigitte Tardy, MD, Resource and Competence Center for Bleeding Diseases, evaluated nonacog alfa pharmacokinetics in real world clinical practice involving patients with hemophilia B receiving prophylaxis.

The team retrospectively collected the FIX values measured during routine visits in patients receiving prophylactic treatment from 2013 to 2019.

All FIX levels were measured via chronometric one-stage assays featuring agents including CK Presto Stago, Pathromtin SL Siemens, and APTT HemosIL. Additional data on age, height, weight, BMI, dose per infusion, and the time of blood sampling after the last infusion were collected.

For patients missing height data, values were estimated via weight percentile-height percentile regression from the National Health and Nutrition Examination Survey (NHANES).

Data on single infusions were lacking, and PK estimates were performed on PK studies that merged observed data from multiple infusions in the same patient.

From there, THL, time to reach 5-2 IU/dl and FIX activity at 48, 72, and 96 hours (h) were derived by Bayesian estimations from a 2-compartment model that accounted fat-free mass as a covariate using NONMEN anaylsis.

A total of 455 patients were included in the study, with infusion data being collected from 64 patients with severe hemophilia B (SBH).

An evaluation of 92 pharmacokinetic (PK) studies found that the median THL was 43.4 h.

A total of 26 patients between .8 and 12 years old at baseline were assessed in 51 PK studies, while 38 patients ages 13-75 years were analyzed in 41 PK studies.

At 72 hours, investigators observed that all FIX values collected in 25 patients were between 1 and 13 IU/dl, and the ranges of nonacog alfa doses in children and adults were 25-96 IU/kg and 30-73 IU/kg, respectively.

Among the 30 FIX values collected in 23 patients (13 children and 10 adults), 25 (11 patients and 8 adults) were between 2 and 10 IU/dl at 96 hours.

Additionally, the ranges of nonacog alfa doses in both children and adults were 23-100 IU/kg and 31-59 IU/kg, respectively.

By 120 hours, 13 of the 20 FIX values collected in 14 patients (5 children and 9 adults) were between 2 and 6 IU/dl.

Investigators suggested that the study confirmed that the time spent with a FIX lebel greater than 2 IU/dl was longer than previously thought.

“These results should be confirmed in a comprehensive PK study of a nonacog alfa with sampling conducted up to day 10 and with centralized determination of FIX activity,” the team wrote.

The study, "Revised terminal half-life of nonacog alfa as derived from extended sampling data: A real-world study involving 64 haemophilia B patients on nonacog alfa regular prophylaxis," was published online in Haemophilia.