Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites.

This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy. A prospective, multicenter PK study was conducted among 59 pregnant women (93.2% white) who were studied once during a trimester. One beverage with 30-95 mg caffeine was consumed, and a blood/urine sample was collected within 1 hour postingestion. Concentrations of caffeine and its primary metabolites were quantified from serum and urine by LC-MS/MS. There was a significant increase in dose-normalized caffeine serum and urine concentrations between the first and third trimesters (P < .05 and P < .01, respectively). Normalized theophylline concentrations also increased significantly in the third trimester in serum (P < .001) and in urine (P < .05). The caffeine urine/serum concentration ratio also increased in the last trimester (P < .05). No significant difference was found in normalized paraxanthine or theobromine concentrations. This study identified decreased caffeine metabolism and an increase in the active metabolite theophylline concentrations during pregnancy, especially in the third trimester, revealing evidence of the large role that pregnancy plays in influencing caffeine metabolism.

Use of methylxanthine therapies for the treatment and prevention of apnea of prematurity.

Apnea of prematurity (AOP) is a common complication of preterm birth, which affects more than 80 % of neonates with a birth weight less than 1,000 g. Methylxanthine therapies, including caffeine and theophylline, are a mainstay in the treatment and prevention of AOP. Despite their frequent use, little is known about the long-term safety and efficacy of these medications. In this review, we systematically evaluated the literature on neonatal methylxanthine therapies and found that caffeine is associated with fewer adverse effects and a wider therapeutic window when compared with theophylline. When used as a therapeutic agent, larger doses of caffeine citrate have been shown to improve acute neonatal outcomes when administered promptly, although further studies are needed to assess the long-term neurological consequences associated with the use of large loading doses. In a secondary analysis of data obtained from a randomized controlled trial, the prophylactic use of caffeine was associated with substantial cost savings and improved clinical outcomes. However, there remains a paucity of well-controlled, randomized clinical trials that have examined the use of caffeine as a prophylactic agent, and further prospective trials are needed to determine if caffeine is a safe and effective prophylactic agent. Additionally, measuring plasma concentrations longitudinally as a marker of therapeutic efficacy and/or toxicity has not been shown to be clinically useful in neonates who are responsive to treatment and exhibit no signs or symptoms of toxicity. However, in cases where toxicity is of concern or for neonates with congenital or pathophysiologic process that may alter the pharmacokinetics of these drugs, therapeutic drug monitoring may be warranted to monitor for methylxanthine toxicity.