Pharmacokinetic dosing in prophylactic treatment of hemophilia A

Abstract

The aim of this study was to investigate individual pharmacokinetics as a tool for dosing of factor VIII (FVIII) in severe hemophilia A. It is assumed that effective prophylaxis against bleedings is maintained if the plasma FVIII:C activity is kept above 1 U/dl, and the present study is based on this assumption. A current standard dosage regimen for FVIII is 25–40 U/kg up to three times weekly. However, there is considerable individual variation in the pharmacokinetics of FVIII:C. Individual pharmacokinetic data were used to computer‐simulate plasma activity curves after repeated doses in 8 patients. Going from prophylaxis regimens of normally 2–3 infusions per week to dosing every 2 days would theoretically reduce their average FVIII consumption by 43% with maintained or increased trough levels of FVIII:C. Daily dosing would reduce their mean FVIII usage by 82%. Modified dosage regimens, infusions every 2 days, were implemented in the patients, and plasma samples were drawn to verify the pharmacokinetic models. The feasibility of the method to generally raise trough levels with a decreased consumption of FVIII was confirmed. Dosing of coagulation factors according to kinetic principles can result in more cost‐effective utilization of these very expensive preparations.

Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia

“…Comparisons between the methodologically most robust studies on either species indicate that the average CL of recombinant FIX is twice as high as that of pdFIX [10]. This difference is confirmed in cross-over comparisons [37,38] [5,10,36]. The difference in CL between rFIX and pdFIX appears to be greater and more consistent between studies, than the difference in half-life, which demonstrate that the comparison cannot be based on only a single PK parameter.…”

“…Initially, simulations demonstrated the potential for more costeffective dosing [5]. Subsequently, a study on 21 patients with severe haemophilia A showed that prophylaxis aimed at targeting a trough level decided by the clinician, based on PK data (based on seven blood samples over 48 h), compared to standard dosing, resulted in a higher mean trough level (2.2 vs. 0.9 IU dL )1…”

“…The frequency of infusions, whilst keeping the total dose of coagulation factor constant, has a large effect on trough levels in patients treated with prophylaxis for both FVIII and IX [5,[7][8][9]13]. If the effect of the half-life and the frequency of dosing are combined, then widely variable amounts of FVIII would be required to maintain the trough FVIII above a predetermined level.…”

“…) )1 and half-life of approximately 12 h. The role of PK for more individualized dosing in clinical practice has been discussed previously [1][2][3][4][5][6][7][8][9][10][11][12][13]. This review aims to summarize our understanding of the influence an individual patientÕs PK on their response to prophylactic treatment.…”

Management of bleeding disorders in children

“…Besides these dosing schedules, pharmacokinetic modelling is sometimes used to calculate doses based on trough FVIII levels [6]. Indeed, it was shown that by increasing dosing frequency from three times per week to once per day, in line with maintained trough levels of FVIII, overall dosing requirements were reduced by 87% (from 6000 to 770 IU week )1 ) [6]. However, trough levels of FVIII are not the only important predictor of dosing requirements, and daily dosing is inconvenient for patients.…”