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

Rivastigmine is a cholinersterase inhibitor approved recently for the treat ment of Alzheimer's disease (AD). The objective of this study is to charact erize the pharmacokinetics-pharmacodynamics of rivastigmine in patients wit h AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for ab out 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentratio ns were determined together with the ACNE activity and computerized neurops ychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivas tigmine 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 bioavai lability 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 p arent 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 w ell with the acetylcholinesterase inhibition, with a ZNS 114-666 concentrat ion of about 5.4 mug/L required for half-maximal inhibition of acetylcholin esterase activity. No statistically significant correlation of the CNTB sco res with enzyme inhibition, parent or metabolite concentration (plasma/CSF) , or rivastigmine dose could be established. The PK-PD model presented in t his study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosi ng recommendations. (C) 2001 the American College of Clinical Pharmacology.