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Paul B. Watkins, MD; Hyman J. Zimmerman, MD; Margaret J. Knapp, PharmD; Stephen I. Gracon, DVM; Karen W. Lewis, MS

JAMA. 1994;271(13):992-998.

Abstract
Objective.
—To characterize the hepatic effects of tacrine treatment in patients with Alzheimer's disease.

Design.
—Controlled trials of tacrine therapy consisting of two blinded, parallel-group trials; three blinded, enrichment-design trials; and their respective open-label extensions.

Setting.
—Multicenter clinical trials in the United States, France, and Canada. Patients.—A total of 2446 men and women at least 50 years of age with a diagnosis of probable Alzheimer's disease of mild to moderate severity and in good health without significant hepatic, cardiovascular, or renal disease.

Intervention.
—Administration of tacrine vs placebo, with weekly measurement of serum hepatic enzymes.

Main Outcome Measures.
—Incidence, maximum severity, and timing of event for serum alanine aminotransferase (ALT) elevation.

Results.
—Among the 2446 patients who received tacrine in clinical trials, ALT levels greater than the upper limit of normal (ULN) occurred on at least one occasion in 1203 patients (49%), ALT levels greater than three times the ULN occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN occurred in 40 patients (2%). The elevated ALT levels were generally asymptomatic and occurred more frequently in women than men. The mean time from initiation of tacrine treatment to first ALT level greater than three times the ULN was 50 days, and 90% of all initial ALT levels greater than three times the ULN occurred during the first 12 weeks of treatment. Of 145 patients who discontinued tacrine treatment because of an ALT level greater than three times the ULN and were rechallenged, 127 (88%) were able to resume long-term therapy with the drug. In all instances, discontinuing tacrine completely reversed elevations in ALT levels, and no deaths related to hepatotoxicity occurred.

Conclusions.
—These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy.

(JAMA. 1994;271:992-998)

Author Affiliations
From the Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor (Dr Watkins); the Clinical Research Department (Drs Knapp and Gracon) and the Department of Biometrics (Ms Lewis), Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Mich; and the George Washington University and Armed Forces Institute of Pathology, Washington, DC (Dr Zimmerman). Drs Knapp and Gracon and Ms Lewis are employees of the Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company and own stock and hold options to purchase further stock in the company. Drs Watkins and Zimmerman have functioned as paid consultants to the Parke-Davis Company regarding the hepatotoxicity of tacrine; however, neither received payments directly related to creation of the manuscript.

Footnotes
Reprint requests to A7119, University of Michigan Hospital, 1500 E Medical Center Dr, Ann Arbor, Ml 48109-0108 (Dr Watkins).

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