Five neonates (4 premature) and 16 infants (6 prematurely born), 15-588 days old, received caffeine as citrate salt for apnea. Plasma samples were collected 0, 2, 4, 6 h after a dose and before the next scheduled one. Patients 8 and 9 were serially studied. Caffeine plasma concentrations were determined using HPLC. The caffeine elimination half-life and clearance varied linearly with gestational age and exponentially with postnatal age, the plateau being reached during the second trimester of life. Dose regimen guidelines as a function of postnatal age were derived from individually calculated doses and dosing intervals in order to achieve, at steady state, a caffeine mean plasma concentration of 11 mg/1 with a minimum of 7.5 mg/l and a maximum of 14.5 mg/l. We suggest dosing intervals for infants before 1 month, 1-2 months, 2-4 months and after 4 months to be equal to 24, 12, 8 and 6 h, respectively. The individual recommended dose varies from 2 to 10 mg/kg (as caffeine base) making caffeine monitoring mandatory in infants.

ABSTRACT. Four premature neonates and eight infants 1-19 months old received caffeine for apnea. The usual morning oral dose was substituted by 1,3,7 I3C-trimethylxanthine (13C-tri CAF) as the citrate salt. Five breath samples were collected the day before (day 1) and the day of 13C-tri CAF administration (day 2). Plasma (after each breath collection) and urine were collected on day 2. 13C-C02 exhalation was determined by isotope ratio mass spectrometry. Caffeine and its metabolites were measured using high-pressure liquid chromatography. Assessment of the labeled C 0 2 in the breath revealed no detectable I3C-tri CAF N-demethylation activity in infants before 45 wk postconceptional age. However, demethylation (as urinary metabolites) has been detected before that age. Two-, 4-, and 6-h cumulative excretion of 13C-tri CAF as 13C-C02 increased with postnatal age and correlated with caffeine plasma clearance (r = 0.840, p c 0.01). These results were consistent with those obtained for urinary metabolites. In one infant (19 months old) the cumulative excretion of I3C-C02 while crying was 65% of the value observed during quiet breathing. The measurement of caffeine demethylation using the caffeine C 0 2 breath test is feasible in infants and is a safe and noninvasive method to determine age related changes in P450I-dependent N-demethylase activity. (Pediatr Res 23: 632-636, 1988)

The maturation of the different pathways of caffeine metabolism was studied during infancy. The group of children (n = 14) consisted of four premature newborn infants and 10 older infants who received caffeine citrate solution. Caffeine and 11 of its metabolites were measured by HPLC. Total demethylation and N3- and N7-demethylation increase exponentially with postnatal age; the plateau is reached by 120 days and accounts for 58.6%, 90.5%, and 79.3%, respectively. N1-demethylation shows no variation with postnatal age. It is suggested that N3-demethylation is more important in young infants than in adults and that maturation of N1-demethylation occurs later than 19 months of age. 8-Hydroxylation is mature as early as 1 month of age and may be higher in infants than in adults. Acetylation is not mature before at least 1 year of age. Differences in maturation rate of acetylation may be related in part to genetic acetylator status.

The maturation of the N-acetyltransferase-dependent AFMU production from caffeine was studied during infancy. The group of children (N = 14) consisted of 4 premature newborn infants and ten 1-19 month-old infants who received caffeine citrate solution for the treatment and prevention of apnea. Caffeine, AFMU, 1X and 9 other metabolites were measured in urine using HPLC. The AFMU/1X ratio did not vary significantly in this population with increasing age. In one of the infants serially studied, the AFMU/1X ratio increased dramatically between 6 and 12 months of age. This observation suggests that the maturation of N-acetyltransferase activity is not completed before 1 year of age implying that acetylator status cannot reliably be determined before that age. Patients studied before 1 year of age whose AFMU/1X ratio was below 0.4 may be either true slow acetylators or still immature fast acetylators.