Implementation of pharmacokinetic-guided dosing of DDAVP and VWF-containing concentrates
in von Willebrand disease

Von Willebrand disease (VWD) is an inherited bleeding disorder, caused by a
deficiency or abnormal function of von Willebrand factor (VWF). In the
circulation, VWF is bound to Factor VIII (FVIII), protecting it from
proteolysis. Severe deficiency of VWF, or a specific defect in interaction with
FVIII, causes a secondary moderate deficiency of FVIII. It is well known that
there is large intra- and interindividual variability in plasma VWF levels, due
to different factors.

Goal of on demand treatment in VWD patients is to stop or prevent (re)bleeding
by increasing or normalizing plasma VWF and FVIII levels. This can be done by
stimulation of the release of endogenous VWF by administration of DDAVP, or by
infusing VWF-containing concentrates. Choice of treatment is dependent on type
of disease, contraindications for DDAVP, and severity of the bleeding or
procedure.

Interindividual response to DDAVP differs greatly, but in general, response in
the individual patient has been proven to be reproducible and consistent over
time. Due to the great interpatient variability in response, a DDAVP test is
required to establish DDAVP response in each individual patient. Patients who
do not adequately respond to DDAVP or have contraindications for its* use are
eligible for treatment with VWF-containing concentrates, that mostly also
contain FVIII. Currently, dosing of medication is based on body weight. During
treatment, daily measurements of plasma FVIII and VWF levels are necessary to
assess the risk of bleeding due to low levels, or risk of thrombosis due to
high levels. From previous research, we know that most VWD patients reach high
to very high FVIII levels during treatment, and could possibly be dosed lower.

Population pharmacokinetic (popPK) models have recently been constructed for
treatment of VWD with DDAVP and VWF-containing concentrates, enabling
individualized dosing in these patients.

To investigate whether on demand dosing using population-based PK-models in VWD
patients is reliable and feasible.

Multicenter, non-randomized, open label, cohort study in VWD patients
undergoing DDAVP-testing and VWD patients requiring treatment with DDAVP and/or
VWF-containing concentrate during a medical intervention or during a bleeding
episode and patients receiving or requiring prophylaxis with VWF containing
concentrate due to frequent bleeding episodes.Frequency and timing, and dosing
(only in case of VWF-containing concentrate treatment) of administration will
be based on a pre-operatively constructed individual PK model.

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

DDAVP-testing:
Newly diagnosed VWD patients undergo DDAVP-testing to investigate the
individual response to DDAVP. In patients needing to undergo a DDAVP-test, a
prediction of the FVIII and VWF:Act levels reached after infusion of DDAVP will
be made on basis of patient characteristics, using the DDAVP population PK
model.

On demand treatment:
Most patients are treated on demand. During elective dental or surgical
procedures and during bleeding episodes, we will aim for FVIII and VWF:Act
target plasma levels as defined in the National Hemophilia Consensus. However,
the treating physician will be able to set specific FVIII and VWF activity
(VWF:Act) target levels if clinically indicated due to the patients* bleeding
phenotype or severity of the procedure or bleeding. These patient specific
target levels will be carefully recorded prior to treatment and communicated to
the clinical pharmacologist performing the PK modeling. The clinical
pharmacologist will provide individualized dosing advices for targeting FVIII
and VWF levels as communicated by the treating physician, based on the PK-model
and daily measurements of FVIII and VWF:Act.

Prophylactic treatment
A few VWD patients receive prophylactic treatment with VWF-containing
concentrate. The aim of prophylactic treatment is to prevent spontaneous
bleeding in VWD patients who experience frequent and/or severe (spontaneous)
bleeding. We will aim for FVIII and VWF:Act target plasma levels as defined in
the National Hemophilia Consensus. However, the treating physician will be able
to set specific FVIII and VWF activity (VWF:Act) target levels if clinically
indicated due to the patients* bleeding phenotype.These patient specific target
levels will be carefully recorded prior to treatment and communicated to the
clinical pharmacologist performing the PK modeling. The clinical pharmacologist
will provide individualized dosing advices for targeting FVIII and VWF levels
as communicated by the treating physician, based on the PK-model and
measurements of FVIII and VWF:Act.


Individual PK profiling:
For every patient an individualized dosing advice will be provided based on
body weight, type of procedure/bleeding, target FVIII and VWF:Act levels
perioperatively/during the bleeding episode, baseline FVIII and VWF:Act level
and individual pharmacokinetic profile.

Individual DDAVP PK profile (DDAVP-test):
DDAVP-tests, which can be seen as an individual DDAVP PK profile, will be
performed according to normal protocol.

Individual VWF-containing concentrate PK profile:
Patients undergoing a medical intervention with replacement therapy with
VWF-containing concentrate, will be asked to undergo a PK profile with
approximately 25 U/Kg Haemate P®. Blood sampling for FVIII and VWF will be
performed before (t=0) and at 4 time points within 48 hours after bolus
infusion; namely t = peak (10 minutes after stop of infusion), t=2-6 hours, t =
approximately 24 hours and t = approximately 48 hours after stop of infusion.
Additional parameters will be tested according to protocol.

Population pharmacokinetic models:
Population PK models for DDAVP and VWF-containing concentrates have been
constructed using the software program NONMEM®. These models are able to
predict average PK parameters for FVIII in a population of VWD patients as well
as the inter- and intra-patient variability of these PK parameters.
In the models the relationship between different patient- and treatment
factors, such as age, weight, baseline FVIII and VWF, blood type and VWF levels
and pharmacokinetic parameters is described. This allows the a priori
prediction of the PK profile of FVIII after DDAVP and VWF-containing
concentrate administration.
Population PK- models for VWF:Act are currently being developed and will be
applicable before start of the study.

There are no additional risks compared to the standard treatment due to
intensive monitoring of FVIII/VWF plasma levels. As it has been shown that
patients are often dosed too high, or to 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/VWF plasma levels, with a possible reduction
of complications and reduction of costs by reducing the amount of factor
concentrate used.
The risks of performing the PK-profile are small (hematoma or inconvenience due
to failure of venipuncture). In young children or 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.