Neurologists were told last week that there have been no cases of liver toxicity
associated with use of the catechol-O-methyltransferase (COMT) inhibitor entacapone
in clinical studies of patients with Parkinson’s disease.
Since the European withdrawal in 1998 of the first COMT inhibitor, tolcapone,
because of hepatotoxicity, there has been concern about the safety of entacapone.
Speaking on October 17 at an Orion/Novartis symposium at the European Federation
of Neurological Societies congress, Professor David Brooks (professor of neurology,
Hammersmith hospital, London) said that in four major phase III studies, involving
800 entacapone and 500 placebo patients, the incidence of liver function test
abnormalities was no different in the entacapone and placebo groups. On present
evidence, there was no need to monitor liver function in patients taking entacapone,
he said.
The most common side effects were dyskinesia and nausea: these were dopaminergic
side effects and could usually be managed by reducing the dose of levodopa.
The most common non-dopaminergic adverse events were loose stools and diarrhoea.
Few patients had had to withdraw from the trials because of side effects.
Entacapone is currently licensed only for use in patients on levodopa with end
of dose motor fluctuations (“wearing off” effects) but it is being
tested in earlier disease in the hope of delaying the onset of levodopa motor
complications. The theory behind early use is that motor problems — a complication
of current levodopa therapy — might be related to pulsatile stimulation
of dopamine receptors. Professor Brooks said that giving entacapone could smooth
out the “peaks and troughs” in plasma levodopa concentrations. A new
trial was planned in which patients would take entacapone from the very first
dose of levodopa, with the aim of producing steady plasma levels.
There was now data showing that entacapone could be used with controlled-release
levodopa formulations. Controlled-release preparations “sat around”
in the bowel where they were metabolised by COMT. Entacapone could inhibit this
bowel metabolism, he said.
Levodopa is usually given with a peripheral dopa-decarboxylase inhibitor to
reduce peripheral metabolism. However, in its presence, levodopa is metabolised
by COMT. Use of a COMT inhibitor, therefore, further increases the amount of
levodopa available to the brain.