CLINICAL-PHARMACOLOGY OF RIVASTIGMINE - A NEW-GENERATION ACETYLCHOLINESTERASE INHIBITOR FOR THE TREATMENT OF ALZHEIMERS-DISEASE

Rivastigmine (ENA 713, or carbamoylatine) is an acetylcholinesterase ( AChE) inhibitor with brain-region selectivity and a long duration of a ction. Both preclinical studies and studies in human volunteers have s hown that rivastigmine induces substantially greater inhibition of ACh E in the central nervous system (CNS) compartment than in the peripher y (40% inhibition of central AChE compared with 10% inhibition of plas ma butylcholinesterase in healthy volunteers). Moreover, rivastigmine preferentially inhibits the G1 enzymatic form of AChE, which predomina tes in the brains of patients with Alzheimer's disease (AD). Evidence from animal studies also suggests that rivastigmine is a more potent i nhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. Absorption of rivastigmine is rapid and almost comple te (>96% of the administered dose). Extensive, saturable first-pass me tabolism, however, leads to bioavailability of approximately 35% of th e administered dose and nonlinear pharmacokinetics. The principal meta bolite of rivastigmine has at least 10-fold lower activity against ACh E compared with the parent drug. Rivastigmine is completely metabolize d; the major route of elimination of the metabolites is renal. Althoug h patients with AD demonstrate 30% to 50% higher plasma concentrations of rivastigmine and its principal metabolite than do healthy elderly patients, there is no evidence of drug accumulation, which is consiste nt with rivastigmine's short pharmacokinetic half-life. Distribution o f rivastigmine into the CNS is extensive, and inhibition of AChE in th e cerebrospinal fluid is detectable 1.2 hours after oral dosing in bot h healthy volunteers and patients with AD. Peak activity is reached so mewhat more slowly in AD patients than in healthy subjects, and the in hibitory effects have a longer duration (6.0 vs 2.4 hours and 12.0 vs 8.5 hours, respectively). Rivastigmine is inactivated during the proce ss of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine. This reduces its propensit y to interact with drugs metabolized by specific CYP-450 isoenzymes. C onsistent with rivastigmine's pharmacokinetic and pharmacodynamic prof iles, Phase II and In. trials have demonstrated that the drug is a wel l-tolerated and effective treatment for AD.