Therapeutic drug monitoring-guided individualized caffeine dosing for apnea of prematurity: Clinical efficacy and association with early neurobehavioral outcomes in preterm infants

Abstract: Background: Given the high incidence of apnea of prematurity (AOP) and the repeated hypoxia-induced nerve damage, treatment optimization from the dosing perspective is critical. Caffeine is the current first-line therapeutic drug for AOP. However, the conventional dose results in low blood concentration compliance, with significant variation among individuals. Objectives: To explore the clinical efficacy and safety of a therapeutic drug monitoring (TDM)-guided individualized caffeine dosage regimen and its association with early neurobehavioral development and weight gain in preterm infants (PTIs). Methods: In this retrospective propensity score-matched cohort study, 130 PTIs with AOP were included after 1:1 matching, with 65 infants in the TDM-guided individualized dosing group and 65 in the conventional fixed-dose group. Inter-group comparative assessments were conducted from the perspectives of blood drug concentration compliance rates, apnea control, adverse reactions, neurobehavioral development scores, clinical outcomes and weight gain rates. Results: Compared with the conventional fixed-dose group, the TDM-guided individualized dosing group had a significantly higher target attainment rate of blood caffeine concentration (92.31% vs 70.77%; OR=5.22, 95% CI 1.68-12.74, P=0.002), lower apnea episode frequency at 4 weeks (MD -1.40 times/day, 95% CI -2.13 to -0.67, P<0.001), lower overall incidence of adverse reactions (6.15% vs 20.00%; OR=0.26, 95% CI 0.09-0.87, P=0.035), higher NBNA score at 40 weeks of corrected gestational age (MD 1.74, 95% CI 1.23-2.25, P<0.001), shorter hospital stay (MD -4.11 days, 95% CI -6.51 to -1.71, P=0.001) and faster weight gain rate (MD 7.88 g/day, 95% CI 3.21-12.55, P=0.001). Conclusion: The TDM-guided individualized caffeine dosing regimen was associated with improved precision of AOP treatment, better short-term therapeutic efficacy and safety, and higher early neurobehavioral assessment scores and weight gain in preterm infants within 6 months of corrected gestational age. Multicenter studies with longer follow-up are needed to further verify its long-term clinical benefits.