H e m a t o lo g y E d u c a t io n - European Hematology Association
H e m a t o lo g y E d u c a t io n - European Hematology Association
H e m a t o lo g y E d u c a t io n - European Hematology Association
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leed. These issues are especially important from an<br />
economical and societal perspective. In clinical practice,<br />
most prophylactic regimens are tai<strong>lo</strong>red to the need of<br />
the individual patient. Methods to deve<strong>lo</strong>p individual<br />
tai<strong>lo</strong>red regimens have included individual pharmacokinetic<br />
data and computer simulated dose level and interval<br />
to achieve a predetermined trough level. 20,21 In both<br />
hemophilia A and B, this has been accomplished with<br />
verificat<strong>io</strong>n of theoretical data through measurement of<br />
actual FVIII/IX levels. Decreasing intervals between prophylactic<br />
doses from 2–3 infus<strong>io</strong>ns weekly to every<br />
other day theoretically reduces average FVIII consumpt<strong>io</strong>n<br />
by 43% with maintained or increased trough FVIII<br />
levels, while daily dosing would reduce mean FVIII<br />
usage by 82%. In Figure 1, the pharmacokinetic profiles<br />
of typical calculat<strong>io</strong>ns in a patient are shown. A modified<br />
dosage regimen with infus<strong>io</strong>ns every other day,<br />
were implemented in a group of Swedish patients with<br />
obtained data supporting the pharmacokinetic models. 21<br />
The feasibility of this method to maintain desired<br />
trough levels with an associated decrease in FVIII consumpt<strong>io</strong>n<br />
was confirmed. Therefore, coagulat<strong>io</strong>n factor<br />
dosing based on pharmacokinetic principles results in<br />
more cost-effective utilizat<strong>io</strong>n of expensive medical<br />
resources.<br />
Inhibitors<br />
Inhibitors deve<strong>lo</strong>p in approximately 30% of patients<br />
with severe hemophilia A and are less common,<br />
approximately 5% in those with severe hemophilia B; 22<br />
a broad range of inhibitor incidence/prevalence has<br />
been reported among different studies. A variety of factors<br />
may impact inhibitor deve<strong>lo</strong>pment, including but<br />
not limited to type of hemophilia, level of deficiency,<br />
specific genetic mutat<strong>io</strong>n, race, immune response genes,<br />
and environmental influences. Among environmental<br />
London, United Kingdom, June 9-12, 2011<br />
issues are included the type of c<strong>lo</strong>tting factor replacement<br />
therapy utilized, such as plasma derived versus<br />
recombinant, intermediate versus high purity products,<br />
treatment regimen (prophylaxis vs. on-demand), age at<br />
start of treatment, and so on. 23-25<br />
During recent years, there has been a vigorous discuss<strong>io</strong>n<br />
as to whether recombinant products are more<br />
immunogenic than plasma-derived intermediate purity<br />
products especially those with intact von Willebrand<br />
factor (VWF). 26-30 Despite this active debate representing<br />
quite different opin<strong>io</strong>ns, present studies reflect a <strong>lo</strong>w<br />
scientific evidence level as no prospective randomized<br />
study has ever been performed addressing this issue.<br />
Based upon this, a recent <strong>European</strong> consensus report<br />
stated that there is no difference in risk of inhibitor<br />
deve<strong>lo</strong>pment between different concentrate types.<br />
Hopefully, the quest<strong>io</strong>n regarding type of concentrate<br />
and rate of inhibitor deve<strong>lo</strong>pment will be finally settled<br />
by the SIPPET study, where classes of products are compared<br />
in a randomized prospective fash<strong>io</strong>n. 31<br />
Issues with current treatments<br />
The main issues can be referred to prophylaxis and to<br />
inhibitor risk and treatment:<br />
• Factor concentrates are distributed by intravenous<br />
inject<strong>io</strong>ns and, as with prophylaxis, this may<br />
become a burden that negatively impacts quality of<br />
life. As prophylaxis should be started early, 12 small<br />
children often are exposed and are in need of ports<br />
to get venous access. This means a surgical procedure<br />
early in life with its risks. Also, surgical procedures<br />
have been suggested to be a risk factor for<br />
inhibitor deve<strong>lo</strong>pment. 32 Novel products with <strong>lo</strong>nger<br />
b<strong>io</strong><strong>lo</strong>gical half-life have a potential to increase convenience<br />
and reduce the need of port implantat<strong>io</strong>ns.<br />
Such products are now in clinical trials.<br />
Figure 1. Computer modeling of pharmacokinetic dosing where PK parameters for the patient are known. Dosing schedules<br />
were modeled to have similar trough levels. Shortening the intervals will dramatically reduce factor consumpt<strong>io</strong>n,<br />
but also peak levels. The clinical impact of the different schedules remains to be evaluated. The standard dose for this<br />
patient is 2000 units 3 times per week (Adopted from ref. 21 ).<br />
Hemato<strong>lo</strong>gy Educat<strong>io</strong>n: the educat<strong>io</strong>n programme for the annual congress of the <strong>European</strong> Hemato<strong>lo</strong>gy Associat<strong>io</strong>n | 2011; 5(1) | 85 |
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