Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease

• Published in: Journal of clinical pharmacology Vol. 41; no. 10; p. 1082
• Main Authors: Gobburu, J V, Tammara, V, Lesko, L, Jhee, S S, Sramek, J J, Cutler, N R, Yuan, R
• Format: Journal Article
• Language: English
• Published: England 01.10.2001
• Subjects: Acetylcholinesterase - cerebrospinal fluid; Aged; Alzheimer Disease - blood; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - enzymology; Alzheimer Disease - metabolism; Carbamates - blood; Carbamates - cerebrospinal fluid; Carbamates - pharmacokinetics; Cholinesterase Inhibitors - blood; Cholinesterase Inhibitors - cerebrospinal fluid; Cholinesterase Inhibitors - pharmacokinetics; Female; Humans; Male; Middle Aged; Models, Biological; Neuropsychological Tests - statistics & numerical data; Patients - statistics & numerical data; Phenylcarbamates; Rivastigmine
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/00912700122012689

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.