Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates

J Pediatr. 2017 Dec;191:50-56.e1. doi: 10.1016/j.jpeds.2017.08.064.


Objective: To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life.

Methods: A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens.

Results: A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L.

Conclusions: To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment.

Keywords: loading dose; maintenance dose; maturation; pharmacokinetics.

MeSH terms

  • Apnea / drug therapy*
  • Birth Weight
  • Caffeine / administration & dosage*
  • Caffeine / pharmacokinetics
  • Caffeine / therapeutic use
  • Central Nervous System Stimulants / administration & dosage*
  • Central Nervous System Stimulants / pharmacokinetics
  • Central Nervous System Stimulants / therapeutic use
  • Citrates / administration & dosage*
  • Citrates / pharmacokinetics
  • Citrates / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Monitoring
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Infant, Premature
  • Infant, Premature, Diseases / drug therapy*
  • Male
  • Weight Gain


  • Central Nervous System Stimulants
  • Citrates
  • Caffeine
  • caffeine citrate