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

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.

Diagnosis of Severe Protein C Deficiency Confirmed by Presence of Rare PROC Gene Mutation

Protein C (PROC) deficiency is caused by mutations in the PROC gene on chromosome 2q14.3. Patients with PROC deficiency typically present distinguished purpura, intracerebral and intravascular coagulopathy, and ophthalmologic complications. Here, we report a rare severe form of PROC deficiency resulting from a compound heterozygosity in PROC. The patient was a 5-day-old female neonate born at 39 weeks of gestation with a birth weight of 2,960 g. She was transferred to our hospital with running a fever at 38.5℃ and with dark red patches on her feet. At admission, a complete blood count showed no specific findings, but levels of PROC and protein S were abnormally low (1% and 68%, respectively). Magnetic resonance imaging revealed intracerebral hemorrhaging and parenchymal damage with dysplasia of the brain. Ophthalmologic examination revealed vitreous hemorrhaging with retinal detachment. Genetic testing revealed a missense mutation (Arg211Trp) and a frameshift mutation (Gly239Serfs*8) in PROC, inherited from the father and mother, respectively. The patient recovered from purpura after undergoing ventriculoperitoneal shunting and treatment with fresh frozen plasma, warfarin sodium, and PROC concentrate. This is the first report of severe neonatal PROC deficiency with purpura fulminans, vitreous hemorrhage, and intracerebral hemorrhage confirmed via PROC genetic testing, which identified a rare compound heterozygosity of PROC.