Theoretical Analysis of Developmental Changes in Adenosine A2A Receptor Occupancy in Premature Infants Under Caffeine Therapy

The aim of this study was to characterize the individual variability in the risk of apnea of prematurity (AOP) during caffeine (CAF) treatment in preterm infants, based on the receptor-occupancy theory accounting for the developmental stage of preterm infants. We constructed a ligand-receptor binding model in which infant growth stage influenced the number of adenosine A2A receptors and CAF pharmacokinetics. Developmental status was represented by gestational age (GA) and postnatal age (PNA). AOP risk was represented by the receptor occupancy of the adenosine A2A receptor of the endogenous neuromodulator adenosine, used here as a mechanistic surrogate whose binding is competitively inhibited by CAF. Model-based calculations demonstrated that receptor occupancy of adenosine varied depending on GA and PNA under standard CAF treatment. Moreover, changes in the receptor occupancy of adenosine were significantly influenced by the rate of adenosine A2A receptor growth. These findings provide a mechanistic basis for understanding how infant growth contributes to individual variability in AOP during CAF therapy.