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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 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 1998 WE MOVE <http://www.wemove.org> janet paterson 52 now / 41 dx / 37 onset snail-mail: PO Box 171 Almonte Ontario K0A 1A0 Canada website: a new voice <http://www.geocities.com/SoHo/Village/6263/> e-mail: <[log in to unmask]>