Pharmacokinetics of Rivastigmine in Healthy Volunteers

Merav Blanca, IIBR (Israel institute for biological research), Ness Ziona, Israel
Miriam Magen, IIBR (Israel institute for biological research), Ness Ziona, Israel
Miriam Herskovitz, IIBR (Israel institute for biological research), Ness Ziona, Israel
Nitzan Tzanani, IIBR (Israel institute for biological research), Ness Ziona, Israel


Rivastigmine tartrate (Exelon®) is a reversible cholinesterase inhibitor prescribed for symptomatic treatment of mild to moderate dementia. It was approved by the FDA for the treatment of Alzheimer’s disease.

In order to evaluate the pharmacokinetic profile (PK) of rivastigmine in healthy population, a clinical study was carried out by the Clinical Research Center at the Tel Aviv Sorasky Medical Center (CRC-TASMC). Fourteen healthy male volunteers have been administered either placebo, 1.5mg or 3mg rivastigmine for 5 consecutive times (every 12 hours) P.O. by a cross over, double blind trial. Blood samples were collected and rivastigmine was extracted from human plasma using liquid-liquid extraction (LLE) when deuterated rivastigmine was used as the internal standard.

A rapid (cycle time = 11 min) and sensitive GC-MS method was developed and validated for the quantitation of rivastigmine in human plasma (LOQ = 0.2 ng/ml). 5 μl of the concentrated extract was analyzed by GC-MS, using EI ionization and SIM mode. Rivastigmine was detected at m/z 235 for rivastigmine and 241 for Rivastigmine-d6. The method proved to be linear within the expected dynamic range (0.2 – 20 ng/ml). Precision coefficients of variation and accuracy bias were less than 20%, as acceptable for similar protocols. Inter-day accuracy bias (for QC samples of 0.5, 2.5 and 10 ng/ml) was less then 10% over the entire trial. Pharmacokinetic profiles were obtained after first and fifth drug administration. Maximum plasma concentrations were obtained between 0.5 and 2 hr. Clearance of rivastigmine from the blood was equally rapid (6-8 hours) and no build-up was observed.