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

J Clin Pharmacol. 2001 Oct;41(10):1082-90. doi: 10.1177/00912700122012689.

Abstract

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.

Publication types

  • Clinical Trial

MeSH terms

  • 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

Substances

  • Carbamates
  • Cholinesterase Inhibitors
  • Phenylcarbamates
  • Acetylcholinesterase
  • Rivastigmine