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Development and verification of a pharmacokinetic model to optimize physiologic replacement of rhIGF-1/rhIGFBP-3 in

Jou-Ku Chung1, Boubou Hallberg2, Ingrid Hansen-Pupp3

  • 1Shire, Lexington, Massachusetts.

Pediatric Research
|November 22, 2016
PubMed

Insights

This study determined optimal dosing for recombinant human insulin-like growth factor-1/recombinant human insulin-like growth factor-binding protein-3 (rhIGF-1/rhIGFBP-3) to maintain physiological serum IGF-1 levels in extremely preterm infants, aiding in retinopathy of prematurity prevention.

Area of Science:

  • Neonatalogy
  • Pharmacokinetics
  • Endocrinology

Background:

  • Retinopathy of prematurity (ROP) is a significant concern in extremely preterm infants.
  • Recombinant human insulin-like growth factor-1/recombinant human insulin-like growth factor-binding protein-3 (rhIGF-1/rhIGFBP-3) is being investigated for ROP prevention.
  • Maintaining physiological intrauterine levels of serum IGF-1 is crucial for development.

Purpose of the Study:

  • To develop a population pharmacokinetic model for rhIGF-1/rhIGFBP-3 in preterm infants.
  • To predict optimal dosing strategies to achieve and maintain target serum IGF-1 levels.
  • To evaluate the efficacy of the determined dosing regimen in a phase II clinical trial.

Main Methods:

  • A population pharmacokinetic model was constructed using data from phase I/II trials and additional studies in preterm infants.
  • Infants with gestational age 23+0 to 27+6 weeks were randomized to receive rhIGF-1/rhIGFBP-3 at a model-predicted dose (250 µg/kg/d continuous i.v. infusion) or standard of care.
  • An interim pharmacokinetic analysis was conducted on the first 10 treated infants to validate the dosing regimen.

Main Results:

  • Serum IGF-1 levels were monitored in 10 treated and 9 control infants.
  • In treated infants, mean serum IGF-1 increased from a baseline of 19.2 µg/l to 45.9 µg/l at 12 hours, remaining within target levels.
  • 88.8% of IGF-1 measurements in treated infants were within the target physiological range, compared to 11.1% in controls.

Conclusions:

  • The study successfully determined appropriate rhIGF-1/rhIGFBP-3 dosing for extremely preterm infants.
  • The established dosing regimen effectively achieved and maintained physiological intrauterine serum IGF-1 levels.
  • This dosing strategy holds promise for the prevention of retinopathy of prematurity.
Abstract

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