NEWS: Entacapone and Tolcapone: PD Congress report

[janet paterson <janet313@xxxxxxxxxxx>]

Entacapone and Tolcapone
PD Congress report, Vancouver, British Columbia, Canada
Sun, 25 Jul 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                 
ifnoneshowupafterayearoftreatment,itisexceedinglyunlikelytheywilllateron.

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 1998 WE MOVE
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janet paterson
52 now / 41 dx / 37 onset
snail-mail: PO Box 171  Almonte  Ontario  K0A 1A0  Canada
website: a new voice <>
e-mail: <janet313@xxxxxxxxxxx>