Pharmacokinetics of rivastigmine and its metabolite in patients with Alzheimer's disease

Rivastigmine (SDZ ENA 713; Exelon®), (+)(S)-N-Ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate, is an acetylcholinesterase inhibitor of the carbamate type approved for the treatment of Alzheimer’s disease. The highest recommended dose of rivastigmine is 6 mg bid; therefore, this open-label, randomized sequence, crossover study was designed to determine the absolute bioavailability of a 6 mg oral dose via comparison with a single 2 mg intravenous dose in patients with probable Alzheimer’s disease who were receiving rivastigmine in a parallel long-term study. A lower intravenous dose was used because a 6 mg intravenous dose could not be given due to tolerability concerns. Serial plasma samples were taken through 12 hours post-dose. The single 6 mg oral dose of rivastigmine was rapidly absorbed, with a mean Tmax of 1.2 hours, a mean T1/2 of 1.7 hours, and a mean Cmax of 25.6 ng/mL. The major metabolite, NAP-226-90, formed by hydrolysis of rivastigmine by cholinesterase, had a mean Tmax of 1.6 hours, a mean T1/2 of 3.6 hours, and a mean Cmax of 11.6 ng/mL. The mean absolute bioavailability of the 6 mg oral dose was 71.7% (range: 21.6–118.5%) when compared to the 2 mg intravenous infusion normalized for dose. The mean AUC0–∝ ratio of NAP 226-90 to rivastigmine was higher with the oral formulation, presumably due to pre-systemic metabolism. The most common adverse event for both formulations was mild to moderate headache (n = 4, 36%). Thus, the 6 mg oral dose of rivastigmine was safe and well-tolerated, with a high bioavailability.