Caffeine Citrate Treatment for Extremely Premature Infants With Apnea: Population Pharmacokinetics, Absolute Bioavailability, and Implications for Therapeutic Drug Monitoring

Abstract

The objective of this study was to develop a population model of the pharmacokinetics (PK) of caffeine after orogastric or intravenous administration to extremely premature neonates with apnea of prematurity who were to undergo extubation from ventilation. Infants of gestational age <30 weeks were randomly allocated to receive maintenance caffeine citrate dosing of either 5 or 20 mg/kg/d. Four blood samples were drawn at prerandomized times from each infant during caffeine treatment. Serum caffeine was assayed by enzyme-multiplied immunoassay technique. Concentration data (431 samples, median: 4 per subject) were obtained from 110 (52 male) infants of mean birth weight of 1009 g, current mean weight (WT) of 992 g, mean gestational age of 27.6 weeks, and mean postnatal age (PNA) of 12 days. Of 1022 doses given, 145 were orogastric, permitting estimation of absolute bioavailability. A 1-compartment model with first-order absorption was fitted to the data in NONMEM. Patient characteristics were screened (P < 0.01) in nested models for pharmacokinetic influence. Model stability was assessed by nonparametric bootstrapping. Clearance (CL) increased nonlinearly with increasing PNA, whereas volume of distribution (Vd) increased linearly with WT, according to the following allometric models: CL (L/h) = 0.167 (WT/70) (PNA/12); Vd (L) = 58.7 (WT/70). The mean elimination half-life was 101. Interindividual variability (IIV) of CL and Vd was 18.8 % and 22.3 %, respectively. Interoccasion variability (IOV) of CL and Vd was 35.1% and 11.1%, respectively. This study established that the elimination of caffeine was severely depressed in extremely premature infants but increased nonlinearly after birth up to age 6 weeks. Caffeine was completely absorbed, which has favorable implications for switching between intravenous and orogastric routes. The interoccasion variability about CL was twice the interindividual variability, which, among other factors, indicates that routine serum concentration monitoring of caffeine in these patients is not warranted.

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

“…The mean clearance estimate was 1.8 mL/h/kg, which was lower than the average clearance values (7.9-8.9 mL/h/kg) reported by other studies 20,25,26) . The estimate of the population mean volume of distribution of caffeine (748 mL/kg) is similar to values reported by other studies (911 mL/kg) 2,27) . For estimation of the parameters in the preterm neonate population, the NONMEM program was used to assess the PK profile information for caffeine.…”

“…The elimination of caffeine was severely suppressed in premature neonates but increased nonlinearly after birth up to 6 weeks of age, and reached adult values at approximately 60 weeks postmenstrual age 2) . The caffeine half-life observed for neonates in this study was shorter than that reported in other studies, which may have been caused by differences in the postnatal days.…”

“…In a study of neonates with GA of 27.6 weeks, groups that maintained caffeine dosing at 5 and 20 mg/kg had a mean serum caffeine concentration of 14.7 µg/mL (4.8-25.1 µg/mL) and 47.4 µg/mL (18.9-79.8 µg/mL), respectively 2) . In another study, the mean serum caffeine levels of 75 preterm neonates were 11.8 µg/ mL (4.75-26.1 µg/mL), with less than 4% >20 µg/mL 20) .…”

“…Premature neonates receive a loading dose of 20-80 mg/kg in the initial 30 minutes, followed by a maintenance dose of 5-20 mg/kg/d 24 hours later 2,3) .…”

Apnea of Prematurity

“…In 1 survey, the majority of neonatologists (approximately 75%) required a 5-to 7-day observation period. 4 Common practice is to initiate this countdown period a few days after discontinuation of caffeine therapy (caffeine half-life, approximately 50-100 hours) 34 and to include only spontaneously occurring (ie, not feeding-related) events.…”