title: Pharmacokinetics and pharmacodynamics of oral mecamylamine - development of a nicotinic acetylcholine receptor antagonist cognitive challenge test using modelling and simulation.
abstract: A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects. A one-compartment linear kinetic model best described the plasma concentrations of mecamylamine. Mecamylamine's estimated clearance was 0.28 ± 0.015 L min-1. The peripheral volume of distribution (291 ± 5.15 L) was directly related to total body weight. Mecamylamine impaired the accuracy and increased the reaction time in tests evaluating short term working memory with a steep increase in the concentration-effect relationship at plasma concentrations below 100 μg L-1. On the other hand, mecamylamine induced a decrease in performance of tests evaluating visual and fine motor coordination at higher plasma concentrations (EC5097 μg L-1). Systolic and diastolic blood pressure decreased exponentially after a plasma mecamylamine concentration of 80 μg L-1, a known effect previously poorly studied in healthy subjects. The developed mecamylamine PKPD model was used to quantify the effects of nicotinic blockade in a set of neurophysiological tests in humans with the goal to provide insight into the physiology and pharmacology of the nicotinic system in humans and the possibility to optimize future trials that use mecamylamine as a pharmacological challenge.
authors.affiliation: 1 Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Alvarez-Jimenez
authors.affiliation: 1 Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Anne Catrien
authors.initials: AC
authors.lastname: Baakman
authors.affiliation: 1 Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Stevens
authors.affiliation: 1 Centre for Human Drug Research, Leiden, the Netherlands.|2 Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Sebastiaan C
authors.initials: SC
authors.lastname: Goulooze
authors.affiliation: 1 Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Ellen P
authors.initials: EP
authors.lastname: Hart
authors.affiliation: 1 Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Rissmann
authors.affiliation: 1 Centre for Human Drug Research, Leiden, the Netherlands.|3 Neurology Department, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Joop Ma
authors.initials: JM
authors.lastname: van Gerven
authors.affiliation: 1 Centre for Human Drug Research, Leiden, the Netherlands.|4 Neurology Department, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Groeneveld
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D006801:Humans; D008297:Male; D008464:Mecamylamine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008570:Memory, Short-Term / Q000187:drug effects; D009538:Nicotine / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D009538:Nicotine
keywords: Mecamylamine; NONMEM; cognitive challenge test; healthy subjects; pharmacokinetic–pharmacodynamic modelling