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The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Plasma samples from nearly all study participants randomized to immediate\u2010release isradipine 5\u2010mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration\u2010time curve. Isradipine exposure parameters were tested for correlations with 36\u2010month changes in disease severity clinical assessment scores, and time\u2010to\u2010event analyses for initiation of antiparkinson therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy\u2010adjusted Unified Parkinson\u2019s Disease Rating Scale parts I\u2013III score over 36\u00a0months (Spearman rank correlation coefficient, <jats:italic>r<\/jats:italic><jats:sub>s<\/jats:sub>: 0.09, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (<jats:italic>r<\/jats:italic><jats:sub>s<\/jats:sub>: 0.18, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36\u00a0months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78\u20130.98, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.02).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link> NCT02168842.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51300","type":"journal-article","created":{"date-parts":[[2021,1,18]],"date-time":"2021-01-18T16:35:24Z","timestamp":1610987724000},"page":"603-612","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Isradipine plasma pharmacokinetics and exposure\u2013response in early Parkinson\u2019s disease"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2394-9513","authenticated-orcid":false,"given":"Charles S.","family":"Venuto","sequence":"first","affiliation":[{"name":"Department of Neurology Center for Health + Technology University of Rochester Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1653-8350","authenticated-orcid":false,"given":"Luoying","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Computational Biology University of Rochester Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Javidnia","sequence":"additional","affiliation":[{"name":"Department of Neurology Center for Health + Technology University of Rochester Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Oakes","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Computational Biology University of Rochester Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"James Surmeier","sequence":"additional","affiliation":[{"name":"Department of Physiology Northwestern University Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Simuni","sequence":"additional","affiliation":[{"name":"Department of Neurology Northwestern University Chicago Illinois 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