caa a22 4500 445314036 CHVBK 20180317142640.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s11095-010-0290-8 doi (NATIONALLICENCE)springer-10.1007/s11095-010-0290-8 A Semi-mechanistic Gastric Emptying Model for the Population Pharmacokinetic Analysis of Orally Administered Acetaminophen in Critically Ill Patients [Elektronische Daten] [Kayode Ogungbenro, Lakshmi Vasist, Robert Maclaren, George Dukes, Malcolm Young, Leon Aarons] ABSTRACT: Purpose: To develop a semi-mechanistic population pharmacokinetic model based on gastric emptying function for acetaminophen plasma concentration in critically ill patients tolerant and intolerant to enteral nutrition before and after prokinetic therapy. Methods: Acetaminophen plasma concentrations were available from a study with 10 tolerant and 20 intolerant patients before and after prokinetic therapy with either erythromycin or metoclopramide. Population pharmacokinetic modelling was carried out in a nonlinear mixed effects analysis software, NONMEM. Results: A four-compartment semi-mechanistic model for stomach, intestine, central and peripheral compartments was described. The rate of emptying of the stomach was described by a first-order rate parameter. The final model has two gastric emptying rate constant parameters: kg1 (1.30h−1, RSE = 53.84%, T1/2 = 0.53h) for the intolerant group before prokinetic therapy and kg2 (27.8h−1, RSE = 59.35%, T1/2 = 0.025h) for both the intolerant group after prokinetic therapy and the tolerant group. Other parameters and estimates (RSE) in the model were ka = 5.12h−1 (28.13%), CL = 13.0L/h (19.62%), CLD = 22.6L/h (19.78%), V1 = 63.8L (12.79%) and V2 = 69L (38.70%). Conclusions: The four-compartment semi-mechanistic population pharmacokinetic model adequately described the data. The gastric emptying half-time is improved by a factor of about 20 in the patients that are intolerant to enteral nutrition after treatment with prokinetic agents. Springer Science+Business Media, LLC, 2010 gastric emptying nationallicence mixed effects modelling nationallicence paracetamol nationallicence population pharmacokinetics nationallicence prokinetic agents nationallicence Ogungbenro Kayode Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Oxford Road, M13 9PT, Manchester, UK aut Vasist Lakshmi GlaxoSmithKline, Research Triangle Park, North Carolina, USA aut Maclaren Robert University of Colorado Health Science Center, Denver, Colorado, USA aut Dukes George GlaxoSmithKline, Research Triangle Park, North Carolina, USA aut Young Malcolm GlaxoSmithKline, Research Triangle Park, North Carolina, USA aut Aarons Leon Centre for Applied Pharmacokinetic Research, The University of Manchester, Oxford Road, M13 9PT, Manchester, UK aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/2(2011-02-01), 394-404 0724-8741 28:2<394 2011 28 11095 https://doi.org/10.1007/s11095-010-0290-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0290-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ogungbenro Kayode Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Oxford Road, M13 9PT, Manchester, UK aut NATIONALLICENCE 700 1- Vasist Lakshmi GlaxoSmithKline, Research Triangle Park, North Carolina, USA aut NATIONALLICENCE 700 1- Maclaren Robert University of Colorado Health Science Center, Denver, Colorado, USA aut NATIONALLICENCE 700 1- Dukes George GlaxoSmithKline, Research Triangle Park, North Carolina, USA aut NATIONALLICENCE 700 1- Young Malcolm GlaxoSmithKline, Research Triangle Park, North Carolina, USA aut NATIONALLICENCE 700 1- Aarons Leon Centre for Applied Pharmacokinetic Research, The University of Manchester, Oxford Road, M13 9PT, Manchester, UK aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/2(2011-02-01), 394-404 0724-8741 28:2<394 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer