Introduction:
Extended half-life factor VIII (FVIII) products currently in development require a careful evaluation of dosing options given that the pharmacokinetics of weekly FVIII levels , including FVIII peak and trough levels, have been shown to play a role in bleeding occurrence.
Methods:
Pharmacokinetic (PK) modeling was conducted using published literature and clinical trial data. Published population PK models for recombinant full length DNA, plasma and albumin free FVIII (octocog alfa, rAHF-PFM) and recombinant B-domain-deleted FVIII Fc fusion product (efraloctocog alfa, rFVIIIFc) were used. All calculations were performed assuming linear pharmacokinetics. Dosing frequencies assessed were every 2 days with rAHF-PFM and every 3, 4, 5 or 7 days with rFVIIIFc. Dosages assessed were 30 IU/kg of rAHF-PFM and 30, 40, 50 or 65 IU/kg of rFVIIIFc. Results were generated for a hypothetical patient aged 30 years, with 70 kg body weight, exhibiting a VWF level of 118 IU/dL and a hematocrit of 45%. Time spent below 1% and 3% per week and time spent above 10% and 20% per week were assessed and compared for each scenario.
Summary:
Compared to 30 IU/kg of rAHF-PFM dosed every other day, a patient on rFVIIIFc would spend more time per week below 1% FVIII level when dosed every 5th day up to 50 IU/kg and when dosed every 7th day at any dose within the range tested. Moreover, even when increasing the dosing frequency to 30 IU/kg of rFVIIIFc every 3rd day, or when dosing rFVIIIFc up to 65 IU/Kg every 4th, 5th and 7th day the patient’s plasma FVIII level will drop below 3%. When looking at time per week spent above higher FVIII levels, the model patient would spend more time above 10% when dosed with rAHF-PFM at 30 IU/kg every second day as compared to rFVIIIFc dosed every 3 days at 30IU/kg, and every 4, 5 and 7 days at any dose within the range tested (≤65 IU/kg). Likewise, this patient will also spend more time above 20% with rAHF-PFM every other day than with rFVIIIFc dosed every 4 days at 40 IU/kg and every 5 days at 50 IU/kg and every 7 days at 65 IU/Kg.
Conclusion:
These data indicate that choice and optimal dosing of FVIII products require a better understanding of individual pharmacokinetics in order to avoid that patients would spend extended time at levels insufficient to protect them from bleeding, particularly subjects with a more active lifestyle.