title: Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease.
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.
authors.affiliation: Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: Gobburu
authors.forename: V
authors.initials: V
authors.lastname: Tammara
authors.forename: L
authors.initials: L
authors.lastname: Lesko
authors.forename: S S
authors.initials: SS
authors.lastname: Jhee
authors.forename: J J
authors.initials: JJ
authors.lastname: Sramek
authors.forename: N R
authors.initials: NR
authors.lastname: Cutler
authors.forename: R
authors.initials: R
authors.lastname: Yuan
mesh_terms: D000110:Acetylcholinesterase / Q000134:cerebrospinal fluid; D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000378:metabolism*; D002219:Carbamates / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D010361:Patients / Q000706:statistics & numerical data; D048448:Phenylcarbamates; D000068836:Rivastigmine
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D000110:Acetylcholinesterase; D000068836:Rivastigmine