Clinical Pharmacokinetics of Caffeine in Korean Preterm Infants with Apnea of Prematurity

Abstract

Purpose: Caffeine shows wide interindividual pharmacokinetic (PK) variation, and therapeutic drug monitoring (TDM) may be needed. The PK profile of caffeine in Korean preterm neonates was investigated, and factors influencing the clearance of caffeine were analyzed. Methods: Fifty-nine preterm neonates receiving caffeine for apnea of prematurity were enrolled in the study (gestational age, 29.5±2.2 weeks and birth weight [BW], 1,318±358 g). Caffeine (20 mg/kg) was intravenously administered to each neonate as a loading dose, followed by a maintenance dose of 5-10 mg/kg/d. A total of 190 serum concentrations were measured for population PK analysis and modeling using nonlinear mixed-effects model (NONMEM ® ) software. Results:The mean serum concentration of caffeine was 15.4±4.5 mg/L (range 7.8-33.0 mg/L). High serum concentrations (>20 mg/L) were noted in 36 samples (29%). At the first measurement of serum caffeine, the mean postmenstrual age was 33.9±2.3 weeks, mean BW was 1,802±471 g, mean duration of treatment was 7.4±9.4 days, and mean sampling time after the last dose was 21.8±2.1 hours. In the population PK analysis, the clearance was 0.033 L/h and volume of distribution was 0.371 L. Typical clearance was calculated as 0.0293×(BW/70) 1.33 . Among the subjects receiving 5 mg/kg/d caffeine, the most significant risk factor associated with high serum concentrations (>20 mg/L) was low BW (P=0.024). Conclusion: BW was the only covariate that influenced caffeine clearance in preterm neonates. Preterm neonates with low BW should be carefully monitored for apnea and adverse reactions in addition to undergoing TDM.

Population pharmacokinetic study of caffeine citrate in Chinese premature infants with apnea

“…The pharmacokinetics parameters of caffeine in preterm neonates of this study were compared with those reported previously (Table 5). Interestingly, we found that the CL value estimated from our study was larger than that of most researches from Australia and Europe, whereas less than the Korean value reported by Lim et al Nevertheless, the value of V in the Korean study was lower than all other researches, in which our value was the largest 6–9,27 . From the available data, it cannot be confirmed whether this phenomenon is due to regional differences or the deviation is resulted from limited subjects.…”

“…A two‐compartment model showed no improvement to OFVs and one‐compartment model with first‐order elimination was successfully fitted to the data, which agreed with the results reported previously 6–9 . Exponential functions were selected to model the inter‐individual variability for CL and residual error.…”

“…The large variable activity of CYP1A2 between subjects influences the disposition of caffeine and might reflect differences linked to sex, race, genetic polymorphisms and other factors 4,5 . There have been reports from Australia, Scotland and Korea on pharmacokinetic study of caffeine in premature infants 6–9 . There are no relevant and exhaustive pharmacokinetic studies of the use of caffeine in Chinese preterm infants probably because the caffeine citrate injection for AOP was not approved for clinical application in China until 2013.…”

Effectiveness and safety of early versus late caffeine therapy in managing apnoea of prematurity among preterm infants: a retrospective cohort study

“…Caffeine has interethnic pharmacokinetic differences. CYP1A2 is the main caffeine metabolism enzyme encoded by the CYP1A2 gene which has gene polymorphism leading to interindividual variability [ 9 , 10 ]. Although a recent study concluded that there was no significant association between CYP1A2 gene variation and caffeine pharmacokinetic parameters [ 10 ], the genetic polymorphisms in caffeine targeting the adenosine receptor induced different clinical responses to caffeine therapy [ 11 , 12 ].…”