Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects

Ricardo Alvarez-Jimenez, Geert Jan Groeneveld, Joop M A van Gerven, Sebastiaan C. Goulooze, Anne Catrien Baakman, Justin L. Hay, Jasper Stevens

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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

LanguageEnglish
Pages1011-1021
Number of pages11
JournalBritish Journal of Clinical Pharmacology
DOIs
Publication statusPublished - 1 Oct 2016

Cite this

@article{b421eee1207b4d63a88a089ac6f82f35,
title = "Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects",
abstract = "Aim: 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. Methods: We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. Results: 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. Conclusions: 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.",
keywords = "ageing, cholinergic dysfunction, healthy subjects, NONMEM, pharmacokinetic–pharmacodynamic modelling, scopolamine",
author = "Ricardo Alvarez-Jimenez and Groeneveld, {Geert Jan} and {van Gerven}, {Joop M A} and Goulooze, {Sebastiaan C.} and Baakman, {Anne Catrien} and Hay, {Justin L.} and Jasper Stevens",
year = "2016",
month = "10",
day = "1",
doi = "10.1111/bcp.13031",
language = "English",
pages = "1011--1021",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell",

}

Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects. / Alvarez-Jimenez, Ricardo; Groeneveld, Geert Jan; van Gerven, Joop M A; Goulooze, Sebastiaan C.; Baakman, Anne Catrien; Hay, Justin L.; Stevens, Jasper.

In: British Journal of Clinical Pharmacology, 01.10.2016, p. 1011-1021.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects

AU - Alvarez-Jimenez, Ricardo

AU - Groeneveld, Geert Jan

AU - van Gerven, Joop M A

AU - Goulooze, Sebastiaan C.

AU - Baakman, Anne Catrien

AU - Hay, Justin L.

AU - Stevens, Jasper

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Aim: 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. Methods: We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. Results: 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. Conclusions: 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.

AB - Aim: 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. Methods: We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. Results: 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. Conclusions: 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.

KW - ageing

KW - cholinergic dysfunction

KW - healthy subjects

KW - NONMEM

KW - pharmacokinetic–pharmacodynamic modelling

KW - scopolamine

UR - http://www.scopus.com/inward/record.url?scp=84986277602&partnerID=8YFLogxK

U2 - 10.1111/bcp.13031

DO - 10.1111/bcp.13031

M3 - Article

SP - 1011

EP - 1021

JO - British Journal of Clinical Pharmacology

T2 - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

ER -