Pharmacokinetic Aspects of Caffeine in Premature Infants

Abstract

The pharmacokinetic profile of caffeine was studied in 15 premature infants. Five infants received a single intravenous dose of 10 mg/kg of caffeine citrate 100% at birth and on the 15th day of life. Ten neonates were studied during daily therapy with caffeine for prophylaxis of idiopathic apnea. The time course of plasma and urinary concentrations of caffeine and theophylline shows that caffeine is transformed to theophylline at birth, while total urinary xanthines decrease significantly (p < 0.001) 72 h after the loading dose given on the 15th day of life. During the whole period of treatment, the decrease in total urinary xanthines and the constant urinary percentage elimination of theophylline are due to further metabolism of theophylline. We confirm that the intravenous loading dose of 10 mg/kg can rapidly obtain therapeutic blood levels of caffeine. We also confirm that the maintenance therapy can be carried out with a single daily dose.

Caffeine Citrate for the Treatment of Apnea of Prematurity: A Double‐Blind, Placebo‐Controlled Study

“…Plasma caffeine content was determined under good laboratory practice (GLP) conditions using a modified highperformance liquid chromatography (HPLC) method. 12 Standard curves ranged from 0.5-50 µg/ml with a sensitivity limit of 0.5 µg/ml. Quality control samples analyzed with each analytic run had coefficients of variation (CVs) less than or equal to 11.6%.…”

Treatment of Apnea of Prematurity

“…[43] The pharmacokinetics of caffeine, like theophylline, are highly variable in the premature neonate. [34,[44][45][46][47][48][49] Gorodischer and Karplus [44] examined pharmacokinetics of caffeine in neonates with a wide range of gestational ages (25-34 weeks). A prolonged half-life of up to 65 hours was noticed in some patients, suggesting a once daily administration regimen.…”

“…[45] Postnatal age, weight at treatment and gestational age may contribute to variability in the clearance of caffeine. [48,49] The slower clearance in the very premature neonate is due to a decreased elimination rate and not an increase in volume of distribution (Vd), since Vd of caffeine is similar in adults and neonates. Adult rates of caffeine elimination are achieved by the neonate by about 3-5 months of age.…”

“…A loading dose of caffeine citrate 20 mg/kg, followed by 5 mg/kg once daily, is a good starting point. [48] Individualization of administration, based on plasma concentrations, appears to be the best method for caffeine administration at this time. Caffeine has an advantage over theophylline in that it has a wider therapeutic index.…”

Caffeine Citrate

“…[41][42][43]45,46] Caffeine is hydrophobic and readily passes through most membranes in the body without accumulating in tissue. [49] In neonates, caffeine is eliminated predominantly via renal excretion according to first-order kinetics; approximately 86% of the drug is excreted unchanged in the urine (within 6 days), [22,44] compared with less than 4% in adults. [40][41][42]47] Caffeine is metabolised in the liver by cytochrome P450 1A2 (CYP1A2); potential metabolic pathways include N-demethylation at positions 1, 3 and/or 7 of the molecule and/or hydroxylation of carbon 8 (see fig.…”