Pharmacokinetic dosing of factor VIII and factor IX in prophylactic treatment of haemophilia

Abstract: The aim of the thesis was to increase cost-effectiveness in prophylactic treatment of haemophilia. Prophylaxis is effective to prevent bleedings and arthropathy, but the high cost limits its use. First, a new distribution system for clotting factor concentrates was implemented in Sweden to improve availability and reduce risks and costs. Next, optimization of dosing in prophylactic treatment was explored. It is assumed that effective prophylaxis is maintained if the plasma FVIII:C or FIX:C activity is kept at or above 1% of normal level. The current standard dosage regimen is 25-40 U FVIII per kg bodyweight three times weekly in haemophilia A and 25-40 U FIX per kg twice weekly in haemophilia B. Since there is considerable individual variation in the pharmacokinetics of FVIII:C and FIX:C, dosing according to bodyweight may result in over or under-dosage if the aim is to reach a certain trough level. Prior to the use of individual pharmacokinetic data in prophylactic treatment, relevant pharmacokinetic parameters had to be determined in methodological studies. The use of in vivo recovery for FVIII:C or FIX:C should be discouraged. Studies of FIX:C should be performed over at least 72 hours. The applicability of single-dose individual pharmacokinetics to predict plasma activity after repeated dosing of FVIII and FIX was confirmed during clinical conditions of prophylactic treatment. Computer-simulations and short-term studies of various dosing regimens indicated substantial potential for increased cost-effectiveness with pharmacokinetically tailored dosing. The clinical feasibility was investigated in a 2 x 6 months randomized, cross-over study of standard vs pharmacokinetic dosing of FVIII completed by 14 patients. The mean trough level of FVIII:C was raised from 0.89% during standard dosing to 2.2% during kinetic dosing. Concomitantly, consumption of FVIII was decreased by one third and the corresponding saving during 6 months was SEK 2.8 million (USD 360 000). The methodology can be used to make the praxis of lifelong prophylaxis more widespread in the haemophilia population of the world.