Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects.
Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure.



We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects.



A two-compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050 l and 62.10 ± 10.100 l, respectively and the clearance was 1.09 ± 0.096 l min(-1) . Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG.



Most of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels.
Centre for Human Drug Research, 2333, CL, Leiden, the Netherlands. ralvarez@chdr.nl.
Ricardo
0000-0001-7581-7566
R
Alvarez-Jimenez
Centre for Human Drug Research, 2333, CL, Leiden, the Netherlands.|Neurology Department, VU University Medical Center, 1081, HV, Amsterdam, the Netherlands.
Geert Jan
GJ
Groeneveld
Centre for Human Drug Research, 2333, CL, Leiden, the Netherlands.|Neurology Department, Leiden University Medical Center, 2333, ZA, Leiden, the Netherlands.
Joop M A
JM
van Gerven
Centre for Human Drug Research, 2333, CL, Leiden, the Netherlands.|Leiden Academic Center for Drug Research, Division of Pharmacology, Faculty of Mathematics and Natural Sciences, Leiden University, 2333, CC, Leiden, the Netherlands.
Sebastiaan C
0000-0003-3369-6107
SC
Goulooze
Centre for Human Drug Research, 2333, CL, Leiden, the Netherlands.
Anne Catrien
AC
Baakman
Centre for Human Drug Research, 2333, CL, Leiden, the Netherlands.
Justin L
JL
Hay
Centre for Human Drug Research, 2333, CL, Leiden, the Netherlands.
Jasper
J
Stevens
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D009483:Neuropsychological Tests; D011930:Reaction Time / Q000187:drug effects; D012438:Saccades / Q000187:drug effects; D012601:Scopolamine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
D018727:Muscarinic Antagonists; D012601:Scopolamine
NONMEM; ageing; cholinergic dysfunction; healthy subjects; pharmacokinetic-pharmacodynamic modelling; scopolamine