title: Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity.
abstract: OBJECTIVE
  The study the population pharmacokinetics of caffeine after intravenous administration to premature infants with apnea.
  
  
  METHODS
  A prospective, blinded parallel study in which daily caffeine citrate doses of 30, 15, and 3 mg/kg were administered over 7 days by intermittent intravenous infusion. Arterial blood samples (three to six per patient) were assayed for caffeine content by means of HPLC. Population pharmacokinetic modeling was performed with NONMEM.
  
  
  RESULTS
  Clearance (L/hr) = (0.00000399 . current weight [grams]) + (0.000128 . postnatal age [days]). For gestational age > 28 weeks, volume of distribution (L) = (0.000764 . weight [grams] + (0.0468 . postnatal age [days]); for gestational age < or = 28 weeks, volume of distribution (L) = (0.000755 . weight [grams]) + (0.0224. postnatal age [days]). Interpatient variability (coefficient of variation, in percent) was approximately 25% for clearance and approximately 11% for volume of distribution. Intrapatient error (standard deviation) was 3.9 mg/L. There was insignificant bias between observed and model-predicated serum caffeine concentrations in a separate group of 30 infants.
  
  
  CONCLUSIONS
  Caffeine was well tolerated at all doses. Clearance was markedly lower and volume of distribution was higher than the values reported previously for term infants and adults. Both parameters were significantly influenced by postnatal age and current body weight, whereas volume of distribution in infants > 28 weeks' gestational age was higher than that in more premature babies. The predictive performance and the clinical application of the derived population models was satisfactorily shown.
authors.affiliation: School of Pharmacy, University of Queensland, St. Lucia, Australia.
authors.forename: T C
authors.initials: TC
authors.lastname: Lee
authors.forename: B
authors.initials: B
authors.lastname: Charles
authors.forename: P
authors.initials: P
authors.lastname: Steer
authors.forename: V
authors.initials: V
authors.lastname: Flenady
authors.forename: A
authors.initials: A
authors.lastname: Shearman
mesh_terms: D001049:Apnea / Q000097:blood*; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000097:blood*; D007262:Infusions, Intravenous; D008297:Male; D011237:Predictive Value of Tests; D011446:Prospective Studies; D015203:Reproducibility of Results; D016037:Single-Blind Method
chemical_list: D002110:Caffeine