[C12] Cancer Biology & Non-infectious Diseases and Medical Sciences

[C12-04] Theoretical Analysis of Caffeine Therapy in Premature Infants Based on the Developmental Effect on Receptor Occupancy

*Haruka Ide¹, Akane Hara¹, Ryosuke Fujihara¹, Kokoro Fukuzawa¹, Masato Taguchi¹ (1. Toyama Univ. (Japan))

Keywords:

Receptor occupancy theory,Growth,Preterm infants,Postmenstrual age,Caffeine,Apnea of prematurity

Apnea of prematurity (AOP) is a common disease in preterm infants. The incidence of AOP decreases as they grow up. Caffeine (CAF) is frequently prescribed for AOP treatment. Although CAF is considered relatively safe and easy to use compared to other drugs with the same indications, a previous study reported that elevated CAF concentrations are associated with tachycardia¹. The efficacy and safety of standard doses of CAF have been confirmed by the available evidence, whereas the dose-response relationship varies among the individuals. To elucidate the mechanism of intersubject variability, we constructed a mathematical model of ligand-receptor binding dynamics reflecting the individual growth stages. We assumed that the pharmacokinetics of CAF and the number of receptors changed depending on the patient’s age. In the simulation, we regarded that postmenstrual age (PMA), which is the sum of gestational age and postnatal age, represents the individual developmental stages. AOP risk was evaluated as the adenosine A2A receptor occupancy by the endogenous neurotransmitter adenosine. The degree of AOP risk varied depending on the PMA. There was a PMA range of increased AOP risk despite CAF treatment. Moreover, the difference in the receptor growth rate and baseline level of the number of receptors had greater effects on the AOP risk particularly at small PMA. The PMA with the high AOP risk, and the PMA where the AOP risk peaked were changed by the various receptor development patterns. Contrarily, a negative AOP risk was observed when receptor growth was slow or the baseline level of the number of receptors was low. It indicated that the CAF treatment may have an excessive effect in certain conditions. These results suggest that developmental changes cause individual differences in the treatment outcomes. This provides general insights into personalized medicine using receptor antagonists according to the biological background of patients.

1) Yu T et al., Incorporating pharmacodynamic considerations into caffeine therapeutic drug monitoring in preterm neonates. BMC Pharmacol Toxicol, 17, 1–8 (2016).