Implementation of pharmacokinetic-guided dosing of prophylaxis in hemophilia patients.

Most severe and some moderate severe hemophilia patients receive prophylactic
treatment with factor concentrate to prevent spontaneous bleeding in joints and
muscles, decreasing the risk of arthropathy and long term disability.
Currently, initial dosing of prophylaxis is based on body weight and, often
hypothetically on maintenance of minimal factor VIII (FVIII) or factor IX (FIX)
concentrate trough levels > 0.01 international units per milliliter (IU/mL) in
both hemophilia A and hemophilia B. However, these trough levels are rarely
measured, and dosing regimens are generally adjusted only when clinically
relevant bleeding occurs, not taking microbleeds into account. Furthermore, it
is well known that a large interindividual variability exists in the
pharmacokinetics (PKs) of factor concentrates in patients. Therefore, besides
an increased awareness of actual FVIII and FIX peak levels, PK-guided dosing of
prophylaxis may lead to more optimal safeguarding of FVIII and FIX trough
levels and may help achieve higher trough and peak levels when clinically
indicated due to activity pattern. In addition, these levels may be achieved
without increasing of the annual FVIII/ FIX concentrate consumption. Moreover,
PK-guided dosing may provide support with regard to the introduction and dosing
of novel extended half-life (EHL) concentrates. In all settings, cost and
benefit of treatment should of course be taken into account. In this study, we
hypothesize that FVIII/FIX trough and peak levels as set by treating physician
can be predicted and achieved effectively by application of PK-guided
prophylactic dosing.
To analyze this, hemophilia patients treated prophylactically will be enrolled
in the study and categorized according to type of hemophilia (hemophilia A or
hemophilia B) and type of concentrate (standard half-life (SHL) or EHL). Severe
hemophilia patients (FVIII/ FIX<0.01 IU/mL) on prophylaxis will be analyzed
separately from non-severe hemophilia patients on prophylaxis (FVIII/ FIX>=0.01
IU/mL).

To investigate the reliability and feasibility of PK-guided prophylactic dosing
of factor concentrates in hemophilia A and B patients (predictive performance).

Multicenter, non-randomized, prospective cohort study in hemophilia patients on
SHL prophylaxes and in hemophilia patients switching to or on EHL prophylaxis.
Frequency and timing, and dosing of administration will be based on constructed
individual PK-profile.


In addition, in those cases where retrospective data of individual patients is
available of administered factor concentrates and achieved FVIII/FIX levels,
this will be utilized to enrich individual PK profiles and to fortify available
population PK models (*real life data*).

All patients will be treated with the same commercially available FVIII/
FIX-containing concentrate as they would be treated with during standard
treatment. Patients will not switch products for study purposes.

PK-profiling:
All individuals will undergo individual PK-profiling according to study
protocol, with infusion of specified dose of factor concentrate and set blood
sampling time points depending on type of hemophilia and type of factor
concentrate.
Doses will be calculated for the FVIII/ FIX target trough and peak values set
by the treating physician, taking patient characteristics and activity pattern
into account and in consultation with patient/ caretakers. In addition, a
dosing regimen will be constructed for treatment of mild, severe and
life-threatening bleedings according to the Dutch National Hemophilia Consensus
and clinical experience.
Dosing regimens will generally be in accordance with the labels of the
administered clotting factors. However in some cases higher doses may be
applied. The latter however can be done safely as FVIII/FIX levels are
monitored.

Initial PK-guided treatment (12 weeks):
Patients will be initially on PK-guided treatment for 12 weeks according to
the constructed dosing regimen. A minimum of three blood sampling moments will
be planned divided over twelve weeks.

Follow-up treatment under PK-guidance (24 weeks):
During last 24 weeks patients will be followed on PK-guided treatment during
prophylaxis. At the end of this follow-up period, blood sampling will be
performed.

MAP Bayesian analysis:
MAP Bayesian analysis will be applied to obtain the individual PK parameters on
basis of the samples obtained from the pharmacokinetic profile. In MAP Bayesian
analysis population PK characteristics are combined with observations
(FVIII/FIX levels) from the studied individual to obtain the most probable
values for its PK parameters. With the derived PK parameters the optimal dosing
regimens can be derived producing adequate exposure. For most products
population PK models are available from literature and will be programmed in
NONMEM software. In cases where no population PK model is available to
determine an individual PK profile, these will be constructed by treatment
sampling, other sources and if necessary through negotiations with
pharmaceutical company.

There are no additional risks compared to the standard treatment due to
intensive monitoring of FVIII/FIX plasma levels. As it has been shown that
patients are often dosed too high or too low, based on their body weight, it is
important to explore other ways of dosing (i.e. PK-guided dosing). This may
enable better targeting of FVIII/FIX plasma levels, with a possible reduction
of complications and reduction of costs by reducing the amount of factor
concentrate used.

Individual PK-profiling will be in all study patients, which may be seen as an
extra burden (hematoma or inconvenience due to failure of venipuncture). In
young children and patients with impaired venous access, we will try to apply a
intravenous catheter, to draw blood at different time points without having to
do repeated punctures. In addition, validation of predicted dosing by extra
blood sampling may also be seen as burden. However, these moments will be
planned efficiently around intravenous infusion of SHL or EHL factor
concentrates. To reduce burden of traveling for patients/ caretakers, blood
sampling moments can be conducted at a patients* home or workplace if preferred
and possible.