RESEARCH PAPER A Semi-mechanistic Gastric Emptying Model for the Population Pharmacokinetic Analysis of Orally Administered Acetaminophen in Critically Ill Patients Kayode Ogungbenro & Lakshmi Vasist & Robert Maclaren & George Dukes & Malcolm Young & Leon Aarons Received: 11 August 2010 / Accepted: 20 September 2010 / Published online: 15 October 2010 # Springer Science+Business Media, LLC 2010 ABSTRACT Purpose To develop a semi-mechanistic population pharma- cokinetic 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 avail- able 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 (1.30 h -1 , RSE= 53.84%, T1/2=0.53 h) for the intolerant group before prokinetic therapy and kg2 (27.8 h -1 , RSE=59.35%, T1/2=0.025 h) for both the intolerant group after prokinetic therapy and the tolerant group. Other parameters and estimates (RSE) in the model were ka=5.12 h -1 (28.13%), CL=13.0 L/h (19.62%), CLD= 22.6 L/h (19.78%), V1=63.8 L (12.79%) and V2=69 L (38.70%). Conclusions The four-compartment semi-mechanistic popu- lation 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. KEY WORDS gastric emptying . mixed effects modelling . paracetamol . population pharmacokinetics . prokinetic agents INTRODUCTION Gastric emptying is the rate at which food and drink leave the stomach. Gastric emptying is important for oral absorption of drugs and nutrients from the small intestine, where absorption is more rapid compared to the stomach (1). Abnormal gastric emptying (slow or rapid) may alter the absorptive process of oral drugs (rate and extent) from the gut and, consequently, affects pharmacokinetics (PK) and pharmacodynamics (PD). Overall drug absorption is gov- erned primarily by the slowest process, and, in such cases, gastric emptying is the rate-limiting step for absorption rate. Rapid and delayed gastric emptying may result in either predisposition to the development of adverse effects of drugs through enhanced peak exposures following rapid release from the stomach or decreased bioavailability and loss of effectiveness. The absorption of many drugs is therefore dependent on the rate of gastric emptying (2). Gastric emptying is the end-result of a complex sequence of K. Ogungbenro (*) Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences The University of Manchester Oxford Road, Manchester M13 9PT, UK e-mail: kayode.ogungbenro@manchester.ac.uk L. Aarons Centre for Applied Pharmacokinetic Research The University of Manchester Oxford Road, Manchester M13 9PT, UK L. Vasist : G. Dukes : M. Young GlaxoSmithKline Research Triangle Park, North Carolina, USA R. Maclaren University of Colorado Health Science Center Denver, Colorado, USA L. Aarons School of Pharmacy and Pharmaceutical Sciences The University of Manchester Oxford Road, Manchester M13 9PT, UK Pharm Res (2011) 28:394–404 DOI 10.1007/s11095-010-0290-8