Tacrine: first drug approved for Alzheimer's disease

To review the pharmacology, biopharmaceutics/pharmacokinetics, clinical efficacy, adverse effects, and therapeutic considerations regarding the use of tacrine in patients with Alzheimer's disease.

Data from the scientific and professional literature were analyzed, interpreted, and summarized. Citations were obtained by performing a MEDLINE search using the following indexing terms: tacrine, tetrahydroaminoacridine, and Alzheimer's drug therapy. Data also were obtained from a summary of the New Drug Application (Summary Basis of Approval of Cognex) and from the approved product labeling.

Studies in Alzheimer's disease have been plagued by methodologic inconsistencies and deficiencies. Only efficacy studies subsequent to the Food and Drug Administration's (FDA) issuance of recommendations for studies in Alzheimer's disease (1991) were used. Therefore, only double-blind, placebo-controlled, parallel design studies of at least three-month's duration using the Alzheimer's Disease Assessment Scale-Cognitive Subscale and the Clinical Interview-Based Impression of Change as efficacy parameters were included.

Trials were assessed according to the criteria listed above. Results were evaluated on the basis of both completed patients and last observation carried forward models.

Tacrine is a cholinesterase inhibitor that increases the availability of acetylcholine in muscarinic neurons. It has a mean bioavailability after oral administration of about 17 percent and an elimination half-life of approximately three hours. Although drug interactions are poorly studied, tacrine is metabolized by isoenzyme P-450IA2 and may interact with other drugs metabolized by this isoenzyme. Tacrine has been shown to have efficacy in mildly to moderately impaired Alzheimer's patients on both psychometric testing and a clinician's structured interview. Although efficacious, its effects are not dramatic, and it does not affect the ultimate course of the disease. Adverse effects are frequent, and significantly elevated hepatic transaminase concentrations may occur in approximately 25 percent of patients.

Tacrine is the first drug approved by the FDA for treatment of Alzheimer's disease. Although it may improve psychometric test scores in mild to moderately impaired patients, it is not a panacea and does not affect the course of the disease. Patients must be monitored closely for elevated transaminase, cholinergic adverse effects, and interactions with drugs metabolized through P-450IA2.