ORIGINAL ARTICLE Population Pharmacokinetics of Omeprazole in Critically Ill Pediatric Patients Maria Jose Solana, MD,* Helena Colom, PhD,† Jesús López-Herce, PhD, MD,* Javier Urbano, MD,* Rafael González, MD,* Jorge López, MD,* Cecilia Manzanares, PhD,‡ and Angel Carrillo, PhD, MD* Background: To develop a population pharmacokinetic model for intravenous omeprazole in critically ill children. Methods: One hundred eighty-six omeprazole concentration-time data from 40 critically ill children were analyzed using the nonlinear mixed-effects approach with the nonlinear mixed-effects modeling software, version 7.2 software. Patients were randomized into 2 groups and received intravenous omeprazole at a dose of 0.5 or 1 mg/kg twice daily. Blood samples were drawn at 0.5, 2, 6, 12, 24, and 48 hours after the first infusion. Results: The pharmacokinetic profile was best described by a 2-compartment model with a first-order elimination process. Between- patient variability could only be associated with plasma clearance (CL). The typical values for plasma CL were 24.9 L$h 21 $70 kg 21 (10.08%), with a distributional clearance of 53.9 L$h 21 $70 kg 21 (11.00%) and central and peripheral compartment distribution vol- umes of 4.23 L/70 kg (19.62%) and 674 L/70 kg (0.89%), respec- tively. Allometric size models seemed to predict changes adequately in all the pharmacokinetic parameters. High values of between-patient variability of CL [75.50% (2.60%)] and residual variability [130.0% (5.26%)] were still found in the final model. Model-based simulations suggested that the most suitable dose was 1 mg/kg because this yielded similar exposure (defined by the area under the concentration-time curve) to that obtained in adults after a 20-mg dose of omeprazole intravenously. Conclusions: An allometric size model allows changes to be predicted in all the pharmacokinetic parameters, making dose adjust- ment by body weight important to achieve the most effective omeprazole exposure. This is the first step toward a population pharmacokinetic study, including more data to develop a predictable model to be used during therapeutic drug monitoring. Key Words: omeprazole, population pharmacokinetics, nonlinear mixed-effects models, critically ill children, therapeutic drug monitoring (Ther Drug Monit 2013;0:1–9) INTRODUCTION Gastrointestinal bleeding in critically ill patients is usually secondary to acute lesions of the gastric mucosa and is associated with increased morbidity and mortality. 1–4 Acid gastric pH is one of the factors that influence the development of acute lesions of the gastric mucosa. 5,6 The proton pump inhibitors (PPIs) are drugs of choice for the prophylaxis and treatment of digestive tract hemorrhage in critically ill patients. 7 There are 5 types of PPI; their pharmacokinetics vary because of differences in their molecular structure. 7 Omeprazole was the first PPI and is still the most widely used. There are very few studies that have analyzed the pharmacokinetics of PPI in children 8–12 and in critically ill patients. 13 Critically ill patients have certain pharmacokinetic char- acteristics that affect the absorption, metabolism, bioavailability, and excretion of drugs. These pharmacokinetic alterations are the result of organ dysfunction (particularly of the liver and kidney), the release of acute-phase reactants, therapeutic interventions and interactions between different drugs. Hypovolaemic states, heart failure, and the alpha- agonists decrease hepatic blood flow, producing a fall in drug clearance. 14 In contrast, vasodilators favor clearance. 15 Inflammatory cytokines and stress hormones can inhibit cytochrome P450, altering the metabolism of omeprazole. Conjugation is also affected, though to a lesser extent. 15,16 In addition, drug interactions with drugs frequently prescribed to critically ill patients can also affect PPI metabolism. The objective of this study was to investigate the pharmacokinetics of intravenous omeprazole in critically ill children and to analyze the influence of demographic factors (age, weight) and of different doses on the pharmacokinetic behavior of the drug. MATERIAL AND METHODS A prospective, randomized, open-label clinical trial (Eudra-CT no: OM1//2007-006102-19) was performed after approval of the protocol by the hospital ethics committee. Patients admitted to the pediatric intensive care unit whose Received for publication March 10, 2013; accepted November 11, 2013. From the *Paediatric Intensive Care Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain; †Biopharmacy and Pharmacokinetics Department, School of Pharmacy, University of Barcelona, Spain; and ‡Pharmacy Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain. Supported by a grant from the Spanish Health Institute Carlos III (grants N. EC07/90670 and RD08/0072: Maternal, Child Health and Development Network) within the framework of the VI National I + D + i Research Programme (2008–2011). The authors declare no conflicts of interest. Correspondence: Jesús López-Herce, PhD, MD, Servicio de Cuidados Intensivos Pediátricos, Hospital General Universitario Gregorio Marañón, Dr Castelo, 47 28009 Madrid, Spain (e-mail: pielvi@hotmail.com). Copyright © 2013 by Lippincott Williams & Wilkins Ther Drug Monit  Volume 0, Number 0, Month 2013 1 Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.