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In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000\u20133,500 ng\/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100\u2013200 ng\/mL). Population PK\u2010PD analyses were performed on the doxapram PK\u2010CO data and the alfentanil PK\u2010antinociception data. The analyses showed that the doxapram\u2010induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK\u2010PD model effectively drives another PK\u2010PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety.<\/jats:p>","DOI":"10.1002\/cpt.601","type":"journal-article","created":{"date-parts":[[2016,12,21]],"date-time":"2016-12-21T21:36:48Z","timestamp":1482356208000},"page":"115-122","source":"Crossref","is-referenced-by-count":14,"title":["Doxapram\u2010mediated Increase in Cardiac Output Reduces Opioid Plasma Concentrations: A Pharmacokinetic\/Pharmacodynamic\u2013Pharmacokinetic\/Pharmacodynamic Modeling Study in Healthy Volunteers"],"prefix":"10.1111","volume":"102","author":[{"given":"M","family":"Roozekrans","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Olofsen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"van der Schrier","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Boom","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Mooren","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Dahan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,3,25]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3458.2006.00236.x"},{"key":"e_1_2_10_2_1","first-page":"793","volume-title":"Handbook of Physiology, Section 3: The Respiratory System, Volume II: Control of Breathing, Part 2","author":"Pavlin E.","year":"1986"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-3565(25)29802-0","article-title":"Selective respiratory stimulating action of doxapram compared to pentylenetetrazaol","volume":"189","author":"Hirsch H.W.","year":"1974","journal-title":"J. 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