Population PK/PD of Off Label Drugs in Premature Neonates

NCT02421068 | Completed DMC

• 1 other identifier: NL-47440907814
• Study Type: observational
• Target: 246
• Locations: 1 country
• Sites: 4

Brief Summary

This study will provide information on the pharmacokinetics, safety and effectiveness of off--label drugs used in critically ill premature infants: doxapram, fentanyl, midazolam, paracetamol, phenobarbital, sildenafil, levetiracetam, ibuprofen and fluconazole. PK/PD analysis with NONMEM (non-linear mixed effects modelling) will result in (adapted) dosage guidelines, thus contributing towards an improvement in the quality of care and cost efficiency. Furthermore the development of Dried Blood Spot (DBS) analysis is investigated for these drugs as a minimally invasive method for conventional patient care and to perform pharmacological studies in children. The adapted dosage guidelines will be implemented directly into clinical practice in collaboration with the NKFK. Therefore the study is designed as an observational multicenter study to be able to collect sufficient data for the drugs of interest.

Conditions

Premature Birth

Keywords

Paracetamol; Fentanyl; Phenobarbital; Doxapram; Midazolam; Sildenafil; Levetiracetam; Pharmacokinetics; Pharmacology; Fluconazole; Ibuprofen

Outcome Measures

Primary Outcomes (1)

• Clearance, Volume of distribution and covariates for the variability of paracetamol, fentanyl, midazolam, phenobarbital, doxapram, sildenafil, levetiracetam, ibuprofen, and fluconazole in premature born neonates

  Clearance, Volume of distribution and variability in premature born neonates will be calculated by population modelling (NONMEM) of the collected data: drug dosages(mg/kg), measured plasmaconcentrations (mg/L) and their metabolites, and patientcharacteristics (body weight, post natal age, gestational age, renal function, gender)

  Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered

Secondary Outcomes (11)

• EC50 of midazolam on treatment of convulsions

  Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered

• EC50 of phenobarbital on treatment of convulsions

  Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered

• EC50 of levetiracetam on treatment of convulsions

  Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered

• EC50 of fentanyl as analgetic

  Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered

• EC50 of paracetamol as analgetic

  Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered

Other Outcomes (2)

• Development of a minimally invasive Dried Blood Spot analysis method

  Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that the validation of the Dried Blood Spot analysis can take place when a study drug is being administered

• Pharmacogenetic profile

  Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered

Study Arms (1)

Preterm neonates

All neonates that receive at least one of the 9 drugs (phenobarbital, paracetamol, levetiracetam, midazolam, sildenafil, fentanyl, doxapram, ibuprofen, fluconazole) are included in the studied cohort

Eligibility Criteria

• Age: Up to 32 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

preterm newborn infants

You may qualify if:

• prescription of one of the seven drug of interest
• parental informed consent

You may not qualify if:

• \- none

Sponsors & Collaborators

• Sinno H.P. Simons: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Leiden Amsterdam Centre for Drug Research (LACDR): collaborator
• Dutch Knowledge Centre for Pediatric Pharmacotherapy (NKFK): collaborator
• Centre for Human Drug Research, Netherlands: collaborator
• Radboud University Medical Center: collaborator

Study Sites (4)

MUMC

Maastricht, 6229 HX, Netherlands

Location

Radboud UMC

Nijmegen, 6525 GA, Netherlands

Location

Erasmus MC - Sophia Children's Hospital

Rotterdam, 3015 CN, Netherlands

Location

Maxima Medical Center

Veldhoven, 5504 DB, Netherlands

Location

Related Publications (1)

• Smit C, Engbers AGJ, Samiee-Zafarghandy S, van Donge T, Simons SHP, Flint RB, Pfister M, Knibbe CAJ, van den Anker JN. Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why? Neonatology. 2023;120(1):81-89. doi: 10.1159/000526210. Epub 2022 Dec 9.

  PMID: 36502794 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

blood

MeSH Terms

Conditions

Premature Birth

Condition Hierarchy (Ancestors)

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Study Officials

• Ronald de Groot, MD, PhD

  Radboud University Medical Center

  STUDY DIRECTOR

• Dick Tibboel, MD, PhD

  Erasmus Medical Center

  STUDY CHAIR

• David Burger, PharmD, PhD

  Radboud University Medical Center

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 1 Month
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD PhD

Study Record Dates

• First Submitted: September 25, 2014
• First Posted: April 20, 2015
• Study Start: August 1, 2014
• Primary Completion: June 30, 2017
• Study Completion: June 30, 2017
• Last Updated: April 3, 2024

Record last verified: 2024-04

Locations

NL (4)