Pharmacokinetics and -dynamics of intrathecal baclofen therapy in patients with spasticity

Intrathecal baclofen therapy (ITB) has been used since many years to treat
spasticity that doesn't respond to oral baclofen treatment. ITB has been proven
to be safe and effective.
The main problem with ITB therapy is that some of the patients develop
tolerance. This means the effect of baclofen is decreasing, while the dose is
increasing. After a while the spasticity in these patients doesn't respond to
the ITB anymore and returns. It's not clear how tolerance develops, which
patients develop it and how it can be treated.

In this study we try to get a better insight in the phenomenon of tolerance by
gathering pharmacokinetic en -dynamic data from patients receiving ITB-therapy
in combination with baclofen dose and clinical effect. This way we try to
understand the development of tolerance and help to treat or prevent it in the
future. The pharmacokinetic and -dynamic model can be used to calculate the
optimal bolus dose of ITB patients more acurate and more precise, hereby
shortening admission time and improving the inital treatment after pump
implantation.

Normal procedure before pump implantation is as follows:
Patients who have an indication for ITB-therapy are admitted to the hospital
for 2-4 days to test intrathecal baclofen. They receive a bolus of baclofen
through an external intrathecal catheter. On the first day they receive a 25
mcg bolus, this dose is increased with 25 mcg every day (day 2: 50 mcg, day 3:
75 mcg, day 4: 100mcg). As soon as the patient reaches a satisfactory
spasmolytic effect the patient can go home and does not need any further bolus
doses. The patients is put on the list for implantation of the permanent
subcutaneous ITB-pump. The most effective bolus dose during test-infusion is
used to determine the daily dose after pump implantation (hourly dose =
(optimal bolus x 2)/24).
If the patient doesn't reach a satisfactory effect with a bolus of 100 mcg (day
4) the patient isn't suitable for ITB-therapy and therefore won't be put on the
list for implantation of the permanent ITB-pump.

After pump implantation the patient receives 3 monthly follow-up appointments.
At this appointments the daily dose can be adjusted to the patient's needs.

Primary Objective:
Studying the phenomenon of tolerance by evaluating pharmacokinetic- and dynamic
parameters, in patients receiving long-term ITB therapy.

Secondary Objective(s):
1.To specify the intrathecal pharmacokinetics and -dynamics of baclofen.
2.To create a model to predict the optimal dose of baclofen after a single
bolus of baclofen combined with CSF sampling in candidates for ITB-therapy,
hereby shortening the admission time for future ITB-candidates.
3.To study the potency of a fixed bolus dose of baclofen during the first year
after pump-implantation.
4.To gain a comprehension of predictive factors for tolerance, by evaluating
the clinical and pharmacokinetic and -dynamic data of patients who develop
tolerance

In this study 20 candidates with a clinical indication for ITB therapy will
receive a series of test boluses of baclofen to determine the dose with which
they reach the most optimal spasmolytic effect. By taking CSF samples after
each bolus, the pharmacokinetics and -dynamics of intrathecal baclofen can be
studied in detail.

On the first day of their admission for the test-infusion, all patients will
receive two single lumen intrathecal catheters, which are placed using x-ray
guidance. One catheter (tip at Th10) will be used to administer baclofen, the
other (tip at Th12) will be used to take CSF samples. Clinical effect will be
measured by using the Modified Ashworth Scale (MAS, a spasticity scale) and the
Hoffman-reflex (a neurophysiological EMG-test for spasticity). The CSF sample
will be used to measure the baclofen concentration in the CSF.

The patients will receive 4 randomized testboluses of baclofen (25,50,75
microgram, and one day when no bolus is given at all) in 4 days (day 2-5 of the
admission, day 1 is reserved for catheter placement). Randomization will happen
in the hospital pharmacy and is blinded for both patient and physician. All
baclofen used during this test-infusion will have a concentration of 0,05 mg /
ml (the same as during the normal test-infusion). After each bolus clinical
effect is measured (MAS and H-reflex) and 10 liquorsamples will be gathered.
These liquorsamples are analyzed for the concentration of baclofen. By
combining baclofen concentration, clinical effect and bolus dose it is possible
to create a model for the pharmacokinetics and -dynamics of intrathecal
baclofen. The model will be cross-validated for each individual patient. The
resulting model can be used to improve the admission time and accuracy of
future ITB test-infusions.

After a succesfull test-infusion, a permanent subcutaneous ITB-pump is
implanted. The pump is filled with baclofen in a concentration of 0,5 mg / ml
(the same as during the normal procedure). The first year after
pump-implantation all patients will receive 3 monthly follow-up appointments.
During this appointments the daily baclofen dose can be altered to the patients
needs. Baclofen dose development and clinical effect will be monitored during
this first year after impantation.

To study the change of effect of a fixed bolus during the first year, the
patient will be admitted to the hospital for 1 day (12-24 hours) at four
scheduled time intervals (1 week, 4 weeks, 12 weeks and 1 year after pump
implantation). At these admissions their pump will be put into minimal infusion
mode, so their spasticity will return shortly. After 5 times the half-life
time, all baclofen is washed out of the CSF. At this moment they will receive
their optimal bolus dose of baclofen (determined during the test infusion). By
measuring clinical effect (MAS, H-reflex) we can determine if the potency of a
fixed bolus of baclofen decreases during the first year. The bolus can be given
through the implanted pump, so no additional lumbar punctures will be needed.

There are several interventions as compared to the normal ITB-test-infusion
protocol.

Baclofen test-infusion
•Patients will receive an additional intrathecal catheter, the same catheter
that is used during permanent pump-implantation.
•Concerning the boluses of baclofen: The boluses will be (almost) the same as
in the normal test-infusion (25, 50,75 µg (study) vs. 25/50/75/100µg (normal).
During the normal test-infusion, the boluses are administered in an increasing
order (every day the dose is increased with 25 µg). If the patient reaches a
satisfying spasmolytic effect on a dose, this will be considered as the optimal
bolus dose and the patient can return home. In this study the order in which
the boluses are administered will be randomized in a double-blind setting by
the apothecary. Every patient receives each bolus once. One day no baclofen
will be administered at al. This will be the negative control. After 5 days the
optimal bolus dose will be determined, this is the lowest dose at which a
patient reaches optimal spasmolytic effect.
•After each bolus, ten (10 min, 20 min, 40 min, 1 h, 1* h, 2h, 4h, 8h, 12h and
24h after) 1 ml CSF-samples will be gathered, through Th12-catheter. One
sample will be taken before the first bolus, this is the negative control
sample.
•After each bolus clinical effect will be measured four times (after 1, 2, 4
and 8 hours), using the MAS (Modified Ashworth score) and the H-reflex. During
normal procedure the clinical effect is only measured three times after each
bolus. Also the H-reflex (a neurophysiological test) is extra as compared with
the normal procedure.

Follow-up phase
•In the follow-up phase all patients will have scheduled 3 monthly
appointments. This is the same frequency as for regular ITB therapy patients.
•To study the change of effect of a fixed bolus during the first year, the
patient will be admitted to the hospital for 1 day (12-24 hours) at four
scheduled time intervals (1 week, 4 weeks, 12 weeks and 1 year after pump
implantation). At these admissions their pump will be put into minimal infusion
mode, so their spasticity will return shortly. After 5 times the half-life
time, all baclofen is washed out of the CSF. At this moment they will receive
their optimal bolus dose of baclofen (determined during the test infusion). By
measuring clinical effect (MAS, H-reflex) we can determine if the potency of a
fixed bolus of baclofen decreases during the first year. The bolus can be given
through the implanted pump, so no additional lumbar punctures will be needed..

This study protocol closely resembles the protocol of the normal test-infusion
phase. The main risk for the patient will be the placement of an extra
intrathecal catheter. Since there is always a small chance of infection
associated with an external intrathecal catheter, this risk will be doubled for
patients in the study. When the catheter is removed within 5 days after
placement (as will be done in this study) the risk of infection is minimal. To
assure they are placed on the rigth spinal level, both catheter are inserted
using x-ray guidance. During this procedure the patient is exposed to a
radiation dose of 2mSv.
CSF-sampling will be done through this intrathecal catheter, so this won*t
create an extra burden for the patient. After each bolus clinical effect will
be measured 4 times a day, one time more than during standard protocol. Since
all patients will receive all bolus doses in a randomized order, the total
admission time will be 1-2 days longer as compared to the normal procedure. As
a result the patient will also receive 1-2 boluses more than normal.

In the follow-up phase patient are more closely monitored during the first year
after pump-implantation. As a result of this, the patients will have to be
admitted to the hospital for 1 day at 4 follow-up appointments during this
first year.

This study will contribute greatly to the insight in tolerance, a problem that
all ITB-patients (including the patients joining the study) can encounter. By
joining the study patients will contribute to this insight and possible better
treatment option for this problem. Additionaly the patients will contribute to
the creation of a model that will make it possible to determine the optimal
baclofen dose for future ITB-patients more quickly and more accurate.

In conclusion this means the small risks associated with this study are in
proportion to the potential value of the results.

Since the study can only be conducted in patients with spasticity, it is
evident that this study could not be conducted without the participation of
subjects belonging to the current study population.