This page contains a Flash digital edition of a book.
Personalised treatment


Short half-life Long half-life 59h difference 10

Difference in FVIII level at 48h

1 0 10 20 30 40 50 Time (h) Figure 2: Difference in time to reach 1% in patients treated with FVIII according to individual half-lives22,23

disadvantage of allowing periods with low levels, and potentially increases the risk of break-through bleeds. Giving an increased dose of FVIII on a Friday is a common practice. A more cost-effective strategy, and one that results in substantially better factor levels, is to give an extra, lower dose infusion on Saturday or Sunday, depending on when the most activity is anticipated. Infusing on alternate day avoids this problem and some families find this an easy regimen to follow. If alternate prophylaxis is started at a young age, problems with adherence are usually rare. Increasing the frequency of FVIII infusions can be used to maintain a desired trough level whilst using substantially less FVIII or to allow a much higher trough to be achieved with the same amount of concentrate.

Several lines of evidence support the view that individual patients with severe haemophilia should have a personalised prophylactic regimen, which should be regularly reassessed and adjusted throughout life. This regimen should take into account the individual

pharmacokinetics of FVIII, in particular its half-life in blood, which shows wide inter-individual variations and varies over time, the individual bleeding pattern, the

condition of the musculoskeletal system, the level and timing of physical activity.

Opportunities provided by long- acting FVIII concentrates Because of their short half-life in circulation of approximately 12 hours, prophylaxis with currently available FVIII concentrates requires on average 150 to 180 injections per year. More frequent infusions of small doses can maintain or slightly increase the trough levels with a parallel decreased consumption of FVIII. Switching from prophylaxis regimens of normally 2–3 infusions per week to dosing every two days was indeed found to reduce average FVIII consumption by 43% with maintained or increased trough levels of FVIII while daily dosing was found to reduce the mean FVIII usage by 82% (Figure 2).19

However, current

short-acting agents offer limited opportunity to raise significantly trough levels or prolong dosing intervals. In other words, with short-acting concentrates, higher dosing allows to increase through level or dosing interval at the cost of increased use. More frequent infusions of small doses can maintain or increase trough level with a reduced

Table 2: Potential of long-lasting concentrates for tailored treatment Treatment strategies

Potential benefits

Fewer injections than with current regimens

Keeping the same number of injections as current regimens


Better adherence Easier initiation

Decreased treatment burden Higher trough levels

Fewer breakthrough bleeding episodes Fewer subclinical bleeding episodes

60 70 80 90 100 110

consumption but require a very high level of adherence and a good venous access. Clinical trials are ongoing (or have been completed) into modified FVIII products, aiming at improving their pharmacokinetic profiles. These modifications mainly include chemical modification (for example, PEGylation, glyco-PEGylation and polysialylation) or fusion to protein conjugates (for example, Fc-IgG fusion and albumin fusion). These longer half-life products, which require less frequent injections, have an obvious potential for allowing more convenient prophylaxis and improve adherence. However, personalised regimens will certainly be required with these new concentrates. Assuming the dose kinetic curves are similar to existing products, the variability in half-life of long-acting products will probably be amplified. For example, if a concentrate has a half-life of 36 hours (range 24–48 hours), an infusion of 30IU/kg would lead to a variation of 6–11.8 days in the time taken for the FVIII to fall to 1%. This will mean that knowledge of an individual’s PK will become even more important when prescribing these newer concentrates, compared to currently available short-acting products. It is also important to recognise that, by prolonging the half-life, the patient will spend longer time with low factor levels and these will occur during the day and the night. This could be problematic when higher troughs need to be maintained, such as at times of physical activity, in patients with target joints or with repeated breakthrough bleeds. Besides these potential limitations and although not yet supported by evidence, long-acting concentrates could certainly offer several major opportunities to allow more patients to initiate or stay on prophylaxis by decreasing the treatment burden (Table 2). A reduction in the number of infusions would indeed represent a major advantage, not only at the initiation of prophylaxis in small children with difficult venous access, but also later in life, during long-term treatment (since 50–80 fewer injections per year would be required). Long-acting products would also offer the potential for individualised patient-friendly treatment schedules, such as weekly dosing or fortnightly regimens, with a likely better adherence. They might also likely provide better protection for currently on-demand patients with only a limited increase in the number of injections. They could also result in a potential reduction in total


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36