Thrasher Research Fund - Medical research grants to improve the lives of children

Project Details

Early Career

Status: Funded - Closed

Effect of feedings on caffeine pharmacokinetics in premature infants

Lawrence Ku, MD

Summary

BACKGROUND: Nearly all premature infants born at <29 weeks gestational age have apnea of prematurity and are treated with caffeine. Current caffeine dosing regimens result in widely varying systemic exposures, necessitating frequent monitoring and dose adjustments to maintain clinical effectiveness and prevent toxicity. GAP: Prior studies suggest that infant formula enhances the metabolism of caffeine compared to breast milk. However, diet-induced differences in caffeine pharmacokinetics and metabolism remain poorly characterized in premature infants. HYPOTHESIS: Premature infants fed formula will have higher caffeine clearances and increased concentrations of urinary caffeine metabolites compared to infants fed breast milk. METHODS: Aim 1: Caffeine dosing, therapeutic drug monitoring, feeding, and demographic data were collected retrospectively for infants born <29 weeks gestation and with ≥1 serum caffeine concentration collected while admitted to the Duke University Intensive Care Nursery between 2013 and 2014. A population pharmacokinetic model using nonlinear mixed-effects modeling was developed. Covariate effects of postnatal age and formula feeding were evaluated in stepwise fashion. Covariates that reduced the objective function value (∆OFV) >3.84 (P<0.05) were retained for multivariable analysis. Goodness-of-fit plots and visual predictive check were used to evaluate model appropriateness. Aim 2: Infants, born at <29 weeks gestation who were treated with caffeine for apnea of prematurity, were enrolled in the neonatal intensive care units at the University of North Carolina and Duke University Hospitals. Eight-hour urine collections were performed at 2-week intervals through 10 weeks of life. Infant diet (breast milk vs. formula) was collected daily for the duration of the study. Urine samples were analyzed using a Thermo Scientific Accela UPLC system coupled with a Thermo Scientific Finnegan TSQ Quantum Ultra triple quadrupole mass spectrometer. The urinary metabolic ratio (1-MU + 1-MX)/1,7-DMU was used to calculated CYP1A2 activity at each collection time point. RESULTS: Aim 1: Thirty-four premature infants contributed 135 caffeine concentrations. The median gestational age and birth weight were 26 weeks (range: 23-28) and 765 g (480-1330). Twenty (59%) infants were fed formula for ≥3 days and 43 (32%) concentrations were collected during formula feeding. Caffeine population pharmacokinetics were best described by a 1-compartment model. After weight, postnatal age on clearance was most impactful (∆OFV=-131) and was retained. Adding formula feeding on clearance after age suggested increased clearance with formula feedings (Θ=1.21), but was not significant (∆OFV=-3.82) and not retained. The population mean clearance (L/h/kg) was 0.37 x (weight/70)0.75 x (age/33)0.765 and volume of distribution (L/kg) was 93.4 x (weight/70). Aim 2: Data were analyzed for 16 extremely premature infants. The mean gestational age and birth weight were 25 ± 1.1 weeks and 838 ± 2.9 grams, respectively. Eight infants were exclusively breast milk fed for the duration of the study. There was high variability in CYP1A2 activity among all infants at all ages. CYP1A2 activity in breast-fed infants and formula-fed infants appears to be similar over the entire age range examined. IMPACT: The results of the current study suggests that while formula feedings could result in induction of CYP1A2-mediated metabolism of caffeine, the effect may be too small to be detected clinically. Future directions will involve the inclusion of feeding volume and age at formula feedings in the development of the models used to estimate the magnitude of enzyme induction and predict the effect on caffeine metabolism and pharmacokinetics.

Supervising Institution:
Duke University

Mentors
P. Brian Smith

Project Location:
North Carolina

Award Amount:
$26,750