Interaction between Formula Feedings and Caffeine Pharmacokinetics in Premature Infants
L. C. Ku1, P. B. Smith2, M. Cohen-Wolkowiez2, D. R. Thakker1
1
University of North Carolina at Chapel Hill, 2Duke Clinical Research Center
Purpose
Caffeine is almost universally prescribed to extremely premature infants to treat apnea of prematurity, a disease affecting all infants
born at <29 weeks gestation. Previous studies in older infants suggest that formula feedings enhance caffeine metabolism through
induction of CYP1A2, the primary caffeine metabolizing enzyme. Since CYP1A2 expression is reduced at younger ages, it is
unknown whether similar food-drug interactions occur in premature infants. This study was designed to evaluate the effect of formula
feedings on caffeine pharmacokinetics in premature infants.
Methods
Caffeine dosing, therapeutic drug monitoring, feeding, and demographic data were collected from the Electronic Health Record (from
the Duke University Intensive Care Nursery between 2013 and 2014) for infants born <29 weeks gestation whose serum caffeine
concentration was collected once or more. A population pharmacokinetic model using NONMEM v.7.2 (nonlinear mixed-effects
modeling) was developed. Body weight was assumed to be a significant determinant of clearance and volume of distribution, and was
included in the base model. 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 fit.
Results
Thirty-four premature infants contributed 135 caffeine concentrations; median gestational age and birth weight were 26 (range: 23-28)
weeks and 765 (480-1330) g. Twenty (59%) infants received formula and 43 (32%) concentrations were collected during formula
feeding. Among infants who were fed formula, the median age at first formula feeding was 38 (2-73) days. The median caffeine dose
was 5.4 (2-20) mg/kg and 4 (1-11) concentrations per infant were obtained. Caffeine population pharmacokinetics were best
characterized by a 1-compartment model and caffeine apparent clearance (CL/F) increased with increasing postnatal age (CL/F = 0.37
x [weight/70] 0.75 x [age/33] 0.765). Goodness-of-fit plots (Figure 1) and visual predictive check (Figure 2) revealed good model fit.
There was a trend towards increased caffeine CL/F with formula feedings; however, it was not statistically significant.
Conclusion
In premature infants, caffeine CL/F increased with increasing body weight and age. In this small cohort of premature infants, presence
of formula feeding was not associated with caffeine CL/F. Analyses evaluating the effect of feeding volume (dose) and age at formula
feeding (CYP1A2 ontogeny) as potential factors affecting CYP1A2 induction are underway.