Pharmacokinetic Aspects of Theophylline in Premature Newborns

Abstract

To characterize further the pharmacokinetics of theophylline in premature infants, its concentraion in blood was measured by high-pressure liquid chromatography after intravenous infusion given to six apneic premature newborns three to 15 days of age. Theophylline's apparent volume of distribution was 0.690 +/- 0.095 liters per kilogram (mean +/- S.E.), a value similar to that of children, but the half-life (30.2 +/- 6.5 hours) was nine times longer. Blood clearance rate (17.6 +/- 2.3 ml per kilogram per hour) was lower than plasma clearance rate (100 ml per kilogram per hour) of young children. At a total plasma concentration of 17 mg per liter, 56.4 +/- 3.8 and 36.4 +/- 3.8 per cent of the theophylline was bound to adult or full-term cord plasma proteins, respectively. Bilirubin and theophylline did not compete for plasma protein. Calculations suggest that a loading doses of 5.5 mg per kilogram and a maintenance dose rate of 1.1 mg per kilogram per eight hours would achieve and maintain a mean blood concentration of 8 mg per liter (about 10 mg per liter in plasma).

Intake of caffeine and other methylxanthines during pregnancy and risk for adverse effects in pregnant women and their foetuses

“…Kadlec et al (1978) found a mean half-life of 4.9 h for theophylline elimination in a population of 54 children who were between three months and six years old and were given the compound orally. The half-life was much longer, 30 h, in six premature newborn children 3 to 15 days old (Aranda et al, 1976). The main pathway of theophylline metabolism in adult humans agrees fairly well with the pathway of caffeine metabolism.…”

A Randomized, Controlled, Double-Blind Trial Comparing Two Loading Doses of Aminophylline

“…This probably reflects the large variability in volume of distribution reported in neonates and differences between studies in gestational and postnatal age of the participants. 14,17,18 In a small study, Lagercrantz et al 16 found that the optimal effect of theophylline for apnea of prematurity was achieved when its plasma concentration was at least 7.25 g/ml. Also, Muttitt et al reported more than 50% clinical response to theophylline only when a level of about 12.7 g/ml was achieved, although the likelihood of side effects such as tachycardia is much higher above those concentrations.…”

Determinants of the plasma protein binding of theophylline in health.

“…The degree of binding in HSA was very similar to that of plasma at equivalent albumin con0o. al., 1974; Aranda et al, 1976;Piafsky et al, 1977) although not with that of Simons et al (1978) or Mangione et al (1978) who indicated that the percentage unbound might vary by 50 to 100% even in healthy individuals. The reason for such discrepancies is unclear but may also relate to methodological differences.…”