Camilla Flintermann wrote:
>Dear friends-- Here are a few items from the talk which Dominic
Marchese
>gave to our support group (Oxford,Ohio) last week.
>*Comtan / Comtess (Entacapone) is soon to be available in the US , and
like
>Tasmar, will probably still require some liver monitoring
It was my understanding that Entacapone would not require liver
monitoring. Joe Bruman...where are you?
PARKINSON's CONGRESS: Entacapone not likely to lead to liver
complications
VANCOUVER, BC -- July 25, 1999 -- Entacapone is not likely to lead to
the
liver complications seen in some patients taking tolcapone, according to
data presented in a satellite session at the 13th International Congress
on
Parkinson's Disease.
The session was sponsored by Novartis Pharma AG, the manufacturer of
entacapone.
Dr. Esa Heinonen, Vice President for Preclinical Research for Orion
Pharma (Finland) presented data from studies comparing entacapone and
tolcapone,
the two COMT inhibitors currently available for treatment of Parkinson's
disease.
In short-term, high-dose toxicological studies in rats, tolcapone
led to
increased hepatocellular damage plus temperature elevation, while
entacapone
did not.
Heinonen noted that both drugs were well tolerated at lower doses.
Heinonen also reviewed recent studies that may shed light on the
mechanism of tolcapone's hepatotoxicity, and explain why entacapone is
less likely to
induce such damage.
He noted that while the structures of the two drugs are similar,
tolcapone is more lipophilic and more nucleophilic.
Tolcapone, but not entacapone, appears to enter mitochondria once
inside
the liver cell.
Heinonen reviewed a study comparing tolcapone and entacapone with
dinitrophenol (DNP), a compound well-known to shuttle protons across the
mitochondrial membrane, disrupting the proton gradient required for ATP
synthesis, and increasing mitochondrial heat production.
High-dose tolcapone, but not entacapone, causes similar decreases in
mitochondrial membrane potential.
Tolcapone and DNP cause similar liver histopathology, as well.
Clinical data regarding liver toxicity was reviewed by Dr. Paul
Watkins,
Professor of Medicine and Pharmacology and Director of the General
Clinical
Research Center at the University of Michigan Medical Center.
Watkins noted that elevation of serum alanine aminotransferase (ALT)
is
an early, liver-specific marker for hepatocellular injury, and that the
extent
of elevation generally correlates with the extent of toxicity.
By convention, serum ALT more than three times the upper limit of
normal
is considered clinically significant.
Watkins said the general belief among toxicologists is that the
incidence of this level of elevation during clinical trials can predict
the likelihood
that such elevation will occur later during the post-marketing period.
When compared to placebo, the incidence for clinically significant
elevation for tolcapone was 1% at 100 mg, and 3% at 200 mg.
"This fell into the range of relatively low concern for irreversible
liver injury," Watkins said, and is comparable to lovastatin, which has
caused no
deaths due to liver injury to date.
By comparison, the incidence of ALT elevation for tacrine was 25%
during
clinical trials.
Watkins noted that liver abnormalities appear within 6-8 months
after a
patient begins treatment, and that if none show up after a year of
treatment, it is exceedingly unlikely they will later on.
For entacapone, there was no significant elevation in ALT compared
to
placebo during clinical trials.
"To my knowledge," Watkins said, "there has never been a drug that
has
shown no difference in serum ALT elevation at more than thee times the
upper limit
of normal relative to placebo in clinical trials that has gone on to
have a
recognized problem with irreversible liver injury."
Watkins noted the FDA pattern has been to impose a monitoring
schedule
on new drugs after a first-in- class drug shows the potential for
causing liver
problems, even without clinical trial evidence for problems in the
second
drug.
However, the large post-marketing experience with entacapone in
Europe
has shown no incidence of liver-related complications, and this may
influence
the FDA's decision regarding a monitoring schedule for entacapone, which
is
expected to be approved for release in the United States later this
year.
Copyright 1999 WE MOVE
--
Judith Richards, London, Ontario, Canada
[log in to unmask]
^^^^
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