R. Alvarez-Jimenez (1), G. J. Groeneveld (1), J. van Gerven (1), J. Stevens (1).
(1) Centre for Human Drug Research, Leiden, the Netherlands.
Objectives: Scopolamine is a non-selective, muscarinic receptor antagonist that is used in a cholinergic challenge test for cognitive impairment. The test induces memory impairment similar to that seen in dementia or psychiatric diseases. Enhanced sensitivity to scopolamine in elderly has been attributed to a subclinical neuronal cholinergic reduction [1] which has led to dose reduction for this population [2]. The objective of this study was to describe the pharmacokinetics (PK) and pharmacodynamic (PD) effects of scopolamine in subjects in a broad age-range to determine the age-related sensitivity to the drug.
Methods: Data were obtained from four studies performed at CHDR where scopolamine was intravenously infused (15 minutes infusion of 0.5 mg in healthy adults and 0.3 mg in healthy elderly). A population PK-PD analysis was performed using a non-linear mixed effect modelling approach with NONMEM [3]. 139 subjects participated with a mean age of 39 years (min 18; max 78). Three neuro-cognitive PD markers were selected from the NeuroCart test battery: adaptive tracker performance, saccadic peak velocity and the alpha power of the EEG.
Results: A two-compartment PK model driving an indirect response model via an effect compartment best described the observations for all parameters. Clearance of scopolamine was linearly correlated to age and the body weight of the subjects and therefore used as a covariate. For all three PD markers, sensitivity to scopolamine (determined by the individual EC50 parameter estimates) showed no decrease with increasing age.
Conclusions: The PD effects in healthy subjects could be solely contributed to age-dependent differences in exposure rather than age-related hypersensitivity to scopolamine.
References:
[1] Quirion R, Aubert I, Robitaille Y, Gauthier S, Araujo DM & Chabot JG. Neurochemical deficits in pathological brain aging: specificity and possible relevance for treatment strategies. Clin Neuropharmacol. 1990;13 Suppl 3:S73-80.
[2] Flicker C, Ferris SH & Serby M. Hypersensitivity to scopolamine in the elderly. Psychopharmacology (Berl). 1992;107(2-3):437-41.
[3] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 23 (2014) Abstr 3034 [www.page-meeting.org/?abstract=3034]
Poster: Drug/Disease modeling - CNS