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Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates
  1. Samira Samiee-Zafarghandy1,
  2. Tamara van Donge2,
  3. Gerhard Fusch1,
  4. Marc Pfister3,
  5. George Jacob1,
  6. Andrew Atkinson4,
  7. Michael J Rieder5,
  8. Cornelis Smit3,
  9. John Van Den Anker6,7
  1. 1Division of Neonatology, McMaster Children's Hospital, Hamilton, Ontario, Canada
  2. 2Department of Pediatric Pharmacology and Pharmacometrics, UKBB Universitäts-Kinderspital, Basel, Switzerland
  3. 3Department of Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, Basel, Switzerland
  4. 4Pädiatrische klinische Pharmakologie, Universitäts-Kinderspital beider Basel, Basel, Switzerland
  5. 5Department of Pediatrics, London Health Sciences Centre Children's Hospital, London, Ontario, Canada
  6. 6Department of Paediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, Basel, Switzerland
  7. 7Division of Clinical Pharmaoclogy, Children's National Health System, Washington, DC, USA
  1. Correspondence to Dr Samira Samiee-Zafarghandy, Department of Pediatrics, Hamilton, Hamilton, ON L8N 3Z5, Canada; samiees{at}mcmaster.ca

Abstract

Objective Exploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates.

Design Prospective, single-centre, open-label, pharmacokinetics study in preterm neonates.

Setting Neonatal intensive care unit at McMaster Children’s Hospital.

Patients Neonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA.

Methods Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation.

Main outcome measure Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0–72h >900 mg·hour/L).

Results Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours’ postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0–72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure.

Conclusion We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0–72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

  • neonatology
  • pharmacology

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The datasets generated during and/or analysed during the current study are available from the corresponding author (ORCID identifier: https://orcid.org/0000-0001-8385-0657) on reasonable request.

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Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The datasets generated during and/or analysed during the current study are available from the corresponding author (ORCID identifier: https://orcid.org/0000-0001-8385-0657) on reasonable request.

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Footnotes

  • SS-Z and TvD contributed equally.

  • CS and JVDA contributed equally.

  • Contributors SS-Z and JVDA conceptualised the study. SS-Z and AA designed the study. GJ and GF collected the data. GF established and validated the laboratory method. MJR contributed to the design of the study. TvD conducted the literature search and carried out the initial population pharmacokinetic (PK) analysis. TvD and CS performed statistical analyses. AA contributed to the statistical interpretation. SS-Z, CS, MP and JVDA provided relevant input that increased the quality of the manuscript substantially. TvD drafted the initial manuscript. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript.

  • Funding SS-Z is supported by New Investigator Fund, Hamilton Health Sciences. TvD, MP, AA, CS and JVDA are supported by the Eckenstein-Geigy foundation.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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