title: Pharmacokinetic Modeling to Simulate the Concentration-Time Profiles After Dermal Application of Rivastigmine Patch.
abstract: Rivastigmine is an inhibitor of acetylcholinesterases and butyrylcholinesterases for symptomatic treatment of Alzheimer disease and is available as oral and transdermal patch formulations. A dermal absorption pharmacokinetic (PK) model was developed to simulate the plasma concentration-time profile of rivastigmine to answer questions relative to the efficacy and safety risks after misuse of the patch (e.g., longer application than 24 h, multiple patches applied at the same time, and so forth). The model comprised 2 compartments which was a combination of mechanistic dermal absorption model and a basic 1-compartment model. The initial values for the model were determined based on the physicochemical characteristics of rivastigmine and PK parameters after intravenous administration. The model was fitted to the clinical PK profiles after single application of rivastigmine patch to obtain model parameters. The final model was validated by confirming that the simulated concentration-time curves and PK parameters (Cmax and area under the drug plasma concentration-time curve) conformed to the observed values and then was used to simulate the PK profiles of rivastigmine. This work demonstrated that the mechanistic dermal PK model fitted the clinical data well and was able to simulate the PK profile after patch misuse.
authors.affiliation: Drug Metabolism & Pharmacokinetics, Translational Medicine, Novartis Pharma K.K., Tokyo, Japan. Electronic address: sachiko.mita@novartis.com.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Nozaki
authors.affiliation: Drug Metabolism & Pharmacokinetics, Translational Medicine, Novartis Pharma K.K., Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Clinical PK/PD, Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lefèvre
mesh_terms: D000279:Administration, Cutaneous; D061605:Administration, Intravenous; D001682:Biological Availability; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003198:Computer Simulation; D008962:Models, Theoretical; D000068836:Rivastigmine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012869:Skin Absorption; D014018:Tissue Distribution; D057968:Transdermal Patch
chemical_list: D002800:Cholinesterase Inhibitors; D000068836:Rivastigmine
keywords: absorption; clinical pharmacokinetics; physiologically based pharmacokinetic modeling; simulations; transdermal