Niina Kleiber1,2, Elisa Calvier3, Miriam G Mooij2,4, Elke H J Krekels3, Wouter H J Vaes5, Dick Tibboel2, Catherijne A J Knibbe3, Saskia N de Wildt2,6. 1. Division of General Pediatrics and Clinical Pharmacology Unit, Department of Pediatrics, Sainte-Justine Hospital, Université de Montréal, and Sainte-Justine Research Center, Montréal, QC, Canada. 2. Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. 3. Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg, Leiden, The Netherlands. 4. Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre, Leiden, The Netherlands. 5. TNO, Zeist, The Netherlands. 6. Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands.
Abstract
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 C 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 C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and C 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.
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 illchildren 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 illchildren, 0-6 years old, and already receiving IV acetaminophen. INTERVENTIONS: Concomitant administration of an oral C 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 C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and C 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.
Authors: Bianca D van Groen; Esther van Duijn; Arjan de Vries; Miriam G Mooij; Dick Tibboel; Wouter H J Vaes; Saskia N de Wildt Journal: Clin Pharmacol Ther Date: 2020-06-27 Impact factor: 6.875
Authors: Bianca D van Groen; Elke H J Krekels; Miriam G Mooij; Esther van Duijn; Wouter H J Vaes; Albert D Windhorst; Joost van Rosmalen; Stan J F Hartman; N Harry Hendrikse; Birgit C P Koch; Karel Allegaert; Dick Tibboel; Catherijne A J Knibbe; Saskia N de Wildt Journal: Clin Pharmacol Ther Date: 2020-06-28 Impact factor: 6.903