Effectiveness of verapamil in patients with carbamazepine-resistant epilepsy

A significant proportion of patients with epilepsy does not enter long-term
remission despite pharmacotherapy (Shorvon & Luciano 2007). Although there is
no single definition of pharmacoresistant (also known as refractory) epilepsy,
two criteria commonly used to identify patients with pharmaco-resistant
epilepsy are persisting seizures despite the use of two or more adequately
selected antiepileptic drugs (AEDs) and the absence of a significant seizure
free period (Berg & Kelly, 2006). In two hospital based-studies approximately
35% of patients were diagnosed to have pharmacoresistant epilepsy (Kwan &
brodie, 2000; Dlugos et al., 2001).
The underlying mechanisms for pharmacoresistance are often not known: it is
unclear why patients with similar seizure types and/or etiology respond
differently to AEDs. One popular hypothesis is that AEDs inadequately
penetrate across the blood-brain barrier due to multidrug transporters (also
known as the *transporter hypothesis*) (Kahane et al., 2008)). P-glycoprotein
(P-gp) is the drug transporter which is most relevant in this respect. P-gp is
the encoded product of the human multidrug-resistance-1(MDR1) gene. It is an
ATP- and Ca2+-dependent detoxifying pump that extrudes potentially toxic
compounds out of cells, located in gut, blood, kidney, liver and endothelial
cells of the blood brain barrier (6). Many drugs, including cancer drugs and
several AEDs, are substrates of P-gp. Overexpression of P-gp and other drug
transporters has been found in endothelial cells and brain tissue of patients
with refractory epilepsy, removed during epilepsy surgery (Lazarowski et al.,
2007; Kwan & Brodie 2005). Two case reports have been published in which the
administration of the P-gp inhibitor verapamil led to significant improvement
in seizure control (Summers et al. 2004; Ianetti et al., 2005).
Based on these findings, a pilot study was performed in China recently to
evaluate the efficacy of verapamil in 42 patients who did not become seizure
free with carbamazepine (in monotherapy or in combination with another AED).
Thirty-eight patients completed the six month treatment period with verapamil:
4 of these patients became seizure free, 7 experienced a seizure reduction of
75-99% and in 8 patients seizure frequency was reduced by 50-74%. The remaining
patients that completed the trial did not experience a significant seizure
reduction. Two patients withdrew from the study because of adverse effects
(diplopia) and two patients were lost to follow-up. These results are very
promising, but need to be replicated before they can be submitted for
publication, and therefore a similar study will now be carried out in the
Netherlands.

Evaluation of the efficacy and tolerability of adding verapamil to the
antiepileptic drug regimen in patients who did not become seizure free on
carbamazepine.

The study will be conducted at the outpatient department of SEIN in Zwolle.
Eligible patients are identified by their treating physician. Verapamil will
be added to AED regimen in a stepwise fashion: first week 120 mg/day; second
week 240 mg/day; fourth week 360 mg/day; sixth week: 420-480 mg/day. The daily
dosage will be administered in three divided dosages. The baseline seizure
frequency will be determined during a three month baseline period
(retrospectively if possible; prospectively otherwise). During the study.
seizure frequency will be recorded using seizure calendars and adverse effects
will be recorded by use of a questionnaire (10) the titration period and the
six month maintenance period. Before the start of verapamil treatment and at
the end of the titration and maintenance periods, AED serum levels, and blood
counts, liver function tests, kidney function tests will be measured. EKGs will
be recorded and EKGs will be performed. Blood pressure will be measured at
visits to the outpatient clinic. In case of adverse effects, verapamil dosage
can be decreased during the study.
In addition the following data will be recorded per patient:
- Demographics: age, gender.
- Epilepsy characteristics: epilepsy type, duration of epilepsy, etiology.
- Medication: type and number of AEDs used before enrolment.
Outcome analysis
In this mirror-image analysis, patients serve as their own control group in the
assessment of verapamil effectiveness. Treatment with verapamil will be
considered effective if a reduction in seizure frequency of at least 50% is
accomplished during the maintenance period compared the seizure frequency
during the baseline period and if verapamil is continued throughout the
treatment period without dose increases of the AEDs or addition of another AED.
Patients will be classified as seizure free if treatment with verapamil led to
the absence of any type of seizures during the maintenance period.

Addition of verapamil to the epilepsy medciation of patients.

The use of Pgp inhbitors has been evaluated in oncology and withdrawal rates
due to adverse effects were high in these exploratory studies (Kwan & Brodie
2005). In the abovementioned pilot study in Chinese epilepsy patients, only 5%
of patients withdrew due to adverse effects. The proposed study will be carried
out in patients with pharmacoresistant epilepsy; these patients experience a
high burden of disease and often are highly motivated to try new therapies. The
intervention in this study consists of adding verapamil to the antiepileptic
drug regimen of patients. Verapamil is a registered drug in the Netherlands,
which implies the risks of participating in such a study are not
disproportionate.