Population Pharmacokinetics of Antibiotics in Critically Ill Children (POPSICLE) (POPSICLE)

Population Pharmacokinetics of Antibiotics in Critically Ill Children

Infections are common on the Intensive Care for both adult and pediatric patients. Adequately dosing antibiotic treatment is of vital importance but both under- and overdosing is frequent due to pathophysiological changes during critical illness. Moreover, the interplay of age and critical illness is even more understudied.

To optimize antibiotic dosing and outcome of infectious disease, personalized dosing guidelines in critically ill patients are highly needed. In this prospective observational population pharmacokinetic study we will evaluate if target attainment for antibiotics is reached in critically ill children with current dosing guidelines. Using these data, individualized dosing guidelines will be developed.

Study Overview

• Status: Unknown
• Conditions: Critical Illness; Infectious Disease; Children
• Intervention / Treatment: Drug: Pharmacokinetics

Detailed Description

Approximately one third of all critically ill children develop infectious disease related complications. Mortality due to infections can be as high as 30-45%. In up to 41% of adult critically ill patients antimicrobial dosing recommendations are inadequate, as acute kidney injury, augmented renal clearance, inflammatory response and hypoalbuminaemia all contribute to variation in drug concentrations. This is an important reason for antibiotic treatment failure and emergence of resistance.

Data from adults cannot be directly extrapolated to children, due to developmental changes in the processes involved in drug disposition. Moreover, the interplay of age and critical illness is even more understudied. Hence, to optimize antibiotic dosing and outcome of infectious disease, personalized dosing guidelines in critically ill patients are highly needed.

In this prospective observational population pharmacokinetic study we will evaluate if target attainment for antibiotics is reached in critically ill children with current dosing guidelines. Using these data, individualized dosing guidelines will be developed.

Objectives:

To determine the population pharmacokinetics of antibiotics in critically ill pediatric patients to develop individualized dosing guidelines for antibiotics for this population.

Study design:

Observational study with minimal invasive procedures: population pharmacokinetic study.

Study population:

Critically ill children, admitted on the pediatric intensive care unit (PICU), receiving antibiotics.

Study parameters/endpoints:

Primary:

• To estimate population pharmacokinetic parameters for antibiotics

Secondary:

• To determine the target attainment rate of antibiotic exposure
• To design individualized dosing guidelines for antibiotics

Exploratory:

• To describe variability in kidney function
• To explore the relationship of genetic variation with disposition of pharmacokinetics.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525GA
      • Recruiting
      • Radboudumc
      • Contact: Stan JF Hartman, M.D.; Phone Number: +31622739795; Email: Stan.Hartman@radboudumc.nl
      • Principal Investigator: Saskia N de Wildt, prof. M.D.
      • Sub-Investigator: Stan JF Hartman, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Critically ill children receiving antibiotics.

Description

Inclusion Criteria:

• 0 to 18 years of postnatal age;
• >37 weeks of gestational age (in children less than 6 months of postnatal age);
• Admitted to pediatric intensive care unit;
• Indwelling central line or arterial line in place for clinical purposes, or regular blood work for clinical reasons;
• Antibiotic therapy already prescribed by treating physician;
• Written informed consent (IC).

Exclusion Criteria:

• Language or cognitive inability to understand written and oral informed consent.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

1; Pharmacokinetics

Drug: Pharmacokinetics; Blood samples are drawn for pharmacokinetic properties of antibiotics during routine care treatment; Blood samples for relevant covariates of drug disposition (kidney function, liver enzymes, C-reactive protein (CRP), albumin); Whole blood is stored for DNA analysis; Urine is drawn from catheter for more detailed estimation of glomerular filtration rate and drug metabolite analysis; Other Names: Antibiotics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of distribution of antibiotics in critically ill children	Population mean value of volume of distribution of antibiotics during critical illness. Mean population volume of distribution will be derived from pooled data of antibiotic concentrations. Covariates of influence on volume of distribution will be incorporated within a population pharmacokinetic model.	14 days
Clearance of antibiotics in critically ill children	Population mean value of clearance of antibiotics during critical illness. Mean population clearance will be derived from pooled data of antibiotic concentrations. Covariates of influence on drug clearance will be incorporated within a population pharmacokinetic model.	14 days

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Saskia N de Wildt, Prof. M.D., Radboud University Medical Center

Publications and helpful links

General Publications

• Hartman SJF, Upadhyay PJ, Mathôt RAA, van der Flier M, Schreuder MF, Brüggemann RJ, Knibbe CA, de Wildt SN. Population pharmacokinetics of intravenous cefotaxime indicates that higher doses are required for critically ill children. J Antimicrob Chemother. 2022 May 29;77(6):1725-1732. doi: 10.1093/jac/dkac095.
• Hartman SJF, Upadhyay PJ, Hagedoorn NN, Mathot RAA, Moll HA, van der Flier M, Schreuder MF, Bruggemann RJ, Knibbe CA, de Wildt SN. Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study. Clin Pharmacokinet. 2021 Oct;60(10):1361-1372. doi: 10.1007/s40262-021-01035-9. Epub 2021 May 26.

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2017
• Primary Completion (Anticipated): May 1, 2020
• Study Completion (Anticipated): October 1, 2020

Study Registration Dates

• First Submitted: August 2, 2017
• First Submitted That Met QC Criteria: August 9, 2017
• First Posted (Actual): August 14, 2017

Study Record Updates

• Last Update Posted (Actual): March 13, 2020
• Last Update Submitted That Met QC Criteria: March 12, 2020
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Critically ill children; Anti-Bacterial agents
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Critical Illness; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: 2016-3085

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No