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Personalised treatment


found to be an independent predictor for development of arthropathy, being more important than the regimen adopted (dose and frequency of infusions).6


joints, while infusing less FVIII than usually required for traditional prophylaxis.18 These data clearly show the


Thus,


taking an early start of prophylaxis for granted, it was hypothesised that the regimens could be personalised on the basis of the patient’s bleeding pattern. These observations led to the developement of incremental dosing or ‘tailored prophylaxis’ approaches. This strategy has been frequently adopted to reduce problems with venous access and education for home treatment at the start of prophylaxis at a very early age. A standardised stepwise approach has been proposed in Canada,18


where children 26


between one and two years of age start prophylaxis with 50 IU/kg once weekly (step 1). Patients are monitored at three-monthly intervals and those who experience three bleeds in the same joint or four total bleeds in the three months from the preceding control have their prophylactic dose increased to 30 IU/kg twice weekly (step 2) and then to 25 IU/kg every other day (step 3). A recent interim analysis found that most boys with severe haemophilia A treated with tailored prophylaxis have little bleeding and good


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importance of an individual tailoring of prophylactic therapies rather than using the same regimen for all patients with severe haemophilia.


Variability and individualisation In the 1990s, a Swedish group described considerable inter-individual variation in required doses of FVIII or FIX and reported that tailoring the dose of clotting factor according to the pharmacokinetics (PK) of FVIII-FIX in the individual patients could raise trough levels with a saving of factor concentrates.19


More


PK data from 44 children (1 to 6 years of age) and an other 99 patients (10 to 65 years of age) on prophylaxis with a recombinant FVIII product showed a direct relationship between the number of total and joint bleeds with the time spent with FVIII levels below 1 IU/dL. In addition to the lack of adherence to the prescribed infusions, FVIII half-life and clearance were significant determinants,


recent studies have confirmed the importance of an approach that is ‘personalised’ on the basis of individual PK.20,21


particularly in children aged one to six years of age of the time spent below 1%. Time spent below a certain factor level and the trough FVIII level depend not only on the dose and the frequency of FVIII infusions but also on the individual PK response to infused FVIII. However, this response is highly variable, particularly in children, and ranges from 6–7 hours to more than 20 hours.20,21 Although standard prophylaxis is prescribed on the basis of the body weight, neither the recovery nor the half-life of FVIII, however, are directly proportional to weight and both vary between patients. As a result, the trough level achieved following an infusion of FVIII shows wide variations. For example, it has been found that, in an adult who has received an infusion of 30 IU/kg, the FVIII level at 48h may vary between 2–12% and the time to reach 1% can vary between 51–110h (Figure 1).22,23


The


standard regimen of 20–40 IU/kg on alternate days is predicted to maintain a trough of above 1 IU/dL in almost all young children but, in adults, who have substantially longer half-lives24,25


, the


median trough at 48h has been shown to be >6 IU dL.11


Given this substantial inter-patient variability in the amount of


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