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Enteral Acetaminophen Bioavailability in Pediatric Intensive Care Patients Determined With an Oral Microtracer and Pharmacokinetic Modeling to Optimize Dosing

Kleiber, Niina PhD1,2; Calvier, Elisa PhD3; Mooij, Miriam G. PhD2,4; Krekels, Elke H. J. PhD3; Vaes, Wouter H. J. PhD5; Tibboel, Dick PhD2; Knibbe, Catherijne A. J. PhD3; de Wildt, Saskia N. PhD2,6

doi: 10.1097/CCM.0000000000004032
Online Clinical Investigations

Objectives: Decreasing morbidity and mortality by rationalizing drug treatment in the critically ill is of paramount importance but challenging as the underlying clinical condition may lead to large variation in drug disposition and response. New microtracer methodology is now available to gain knowledge on drug disposition in the intensive care. On the basis of studies in healthy adults, physicians tend to assume that oral doses of acetaminophen will be completely absorbed and therefore prescribe the same dose per kilogram for oral and IV administration. As the oral bioavailability of acetaminophen in critically ill children is unknown, we designed a microtracer study to shed a light on this issue.

Design: An innovative microtracer study design with population pharmacokinetics.

Setting: A tertiary referral PICU.

Patients: Stable critically ill children, 0–6 years old, and already receiving IV acetaminophen.

Interventions: Concomitant administration of an oral 14C radiolabeled acetaminophen microtracer (3 ng/kg) with IV acetaminophen treatment (15 mg/kg every 6 hr).

Measurements: Blood was drawn from an indwelling arterial or central venous catheter up to 24 hours after 14C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and 14C concentrations by accelerated mass spectrometry.

Main Results: In 47 patients (median age of 6.1 mo; Q1–Q3, 1.8–20 mo) the mean enteral bioavailability was 72% (range, 11–91%). With a standard dose (15 mg/kg 4 times daily), therapeutic steady-state concentrations were 2.5 times more likely to be reached with IV than with oral administration.

Conclusions: Microtracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral administration of acetaminophen results in less predictable exposure and higher likelihood of subtherapeutic blood concentration than does IV administration. IV dosing may be preferable to ensure adequate pain relief.

1Division of General Pediatrics and Clinical Pharmacology Unit, Department of Pediatrics, Sainte-Justine Hospital, Université de Montréal, and Sainte-Justine Research Center, Montréal, QC, Canada.

2Intensive Care and Department of Pediatric Surgery, Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands.

3Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg, Leiden, The Netherlands.

4Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Centre, Leiden, The Netherlands.

5TNO, Zeist, The Netherlands.

6Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands.

Drs. Kleiber and Calvier contributed equally to this work.

Drs. Knibbe and de Wildt contributed equally to this work.

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Supported, in part, by grant from The Netherlands Organization for Health Research and Development research grant (113202007).

Drs. Krekels and de Wildt disclosed work for hire. Drs. Vaes’s and de Wildt’s institutions received funding from The Netherlands Organization for Health Research and Development (ZonMw). Dr. de Wildt’s institution also received funding from TNO Zeist (consulting); she disclosed she is Director of the Dutch Knowledge Center for Pharmacotherapy in Children and as such is responsible for the dosing guidelines of paracetamol in the Dutch Pediatric Formulary; and she disclosed off-label product of paracetamol. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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