{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T05:48:43Z","timestamp":1693806523083},"reference-count":37,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,9,27]],"date-time":"2017-09-27T00:00:00Z","timestamp":1506470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Event\u2010related potentials (<jats:styled-content style=\"fixed-case\">ERP<\/jats:styled-content>s) are commonly used in Neuroscience research, particularly the P3 waveform because it is associated with cognitive brain functions and is easily elicited by auditory or sensory inputs. <jats:styled-content style=\"fixed-case\">ERP<\/jats:styled-content>s are affected by drugs such as lorazepam, which increase the latency and decrease the amplitude of the P3 wave. In this study, auditory\u2010evoked <jats:styled-content style=\"fixed-case\">ERP<\/jats:styled-content>s were generated in 13 older healthy volunteers using an oddball tone paradigm, after administration of single 0.5 and 2 mg doses of lorazepam. Population pharmacokinetics (<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>)\/pharmacodynamics (<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>) models were developed using nonlinear mixed\u2010effects methods in order to assess the effect of lorazepam on the latency and amplitude of the P3 waveforms. The <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content> models showed that doses of 0.3 mg of lorazepam achieved approximately half of the maximum effect on the latency of the P3 waveform. For P3 amplitude, half the maximum effect was achieved with a dose of 1.2 mg of lorazepam. The <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content> models also predicted an efficacious dose range of lorazepam, which was close to the recommended therapeutic range. The use of longitudinal P3 latency data allowed better predictions of the lorazepam efficacious dose range than P3 amplitude or aggregate exposure\u2013response data, suggesting that latency could be a more sensitive parameter for drugs with similar mechanisms of action as lorazepam and that time course rather than single time\u2010point <jats:styled-content style=\"fixed-case\">ERP<\/jats:styled-content> data should be collected. Overall, the results suggest that P3 <jats:styled-content style=\"fixed-case\">ERP<\/jats:styled-content> waveforms could be used as potential non\u2010specific biomarkers for functional target engagement for drugs with brain activity, and <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content> models can aid trial design and choice of doses for development of new drugs with <jats:styled-content style=\"fixed-case\">ERP<\/jats:styled-content> activity.<\/jats:p>","DOI":"10.1111\/bcpt.12900","type":"journal-article","created":{"date-parts":[[2017,9,4]],"date-time":"2017-09-04T18:42:37Z","timestamp":1504550557000},"page":"245-252","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Population Pharmacokinetic\/ Pharmacodynamic Modelling of Auditory\u2010Evoked Event\u2010Related Potentials with Lorazepam"],"prefix":"10.1111","volume":"122","author":[{"given":"Aur\u00e9lie","family":"Lombard","sequence":"first","affiliation":[{"name":"Eli Lilly and Company Erl Wood Manor Windlesham UK"},{"name":"Universit\u00e9 de Paris Descartes Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Brittain","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Erl Wood Manor Windlesham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham","family":"Wishart","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Erl Wood Manor Windlesham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Lowe","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Lilly\u2010NUS Centre for Clinical Pharmacology Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Erl Wood Manor Windlesham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Landschulz","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Indianapolis IN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Dorffner","sequence":"additional","affiliation":[{"name":"The Siesta Group Schlafanalyse GmbH Vienna Austria"},{"name":"Medical University of Vienna Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Anderer","sequence":"additional","affiliation":[{"name":"The Siesta Group Schlafanalyse GmbH Vienna Austria"},{"name":"Medical University of Vienna Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunice","family":"Yuen","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Erl Wood Manor Windlesham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,9,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12217"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1037\/0882-7974.16.1.161"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0301-0511(88)90017-8"},{"key":"e_1_2_7_5_1","first-page":"361","volume-title":"Human Event\u2010Related Potentials. 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