Incorporating pharmacodynamic considerations into caffeine therapeutic drug monitoring in preterm neonates

BACKGROUND: This study sought to assess the pharmacokinetic and pharmacodynamic relationships of caffeine citrate therapy in preterm neonates who had therapeutic drug monitoring (TDM) in the post-extubation period. METHODS: A retrospective observational study was conducted in preterm neonates who received caffeine citrate therapy for apnea of prematurity and had TDM done in the post-extubation period between January 2006 and October 2011. The relationships between pharmacodynamic effects (heart rate, respiratory rate, episodes of apnea, adverse events) and caffeine serum concentrations were explored. RESULTS: A total of 177 blood samples were obtained from 115 preterm neonates with a median (range) gestational age of 29 (24 – 33) weeks and birth weight of 1230 (607 – 2304) kg. Caffeine citrate therapy was initiated at a median (interquartile range) postnatal age of 1 (1 – 3) day and TDM was performed at a postnatal age of 15 (10 – 24) days. No direct correlations were found between respiratory rate or apneic episodes and caffeine serum concentrations; however, heart rate and caffeine serum concentrations were significantly correlated (p < 0.05). Dosing regimen of 40/5 mg/kg q12h (loading dose/maintenance dose, time interval) led to similar endotracheal re-intubation rate but increased percentage of patients experiencing tachycardia compared to the standard regimen of 20/5 mg/kg q24h (44.7 % vs 10.2 %, p < 0.001). CONCLUSION: Based on this retrospective study, no correlation between episodes of apnea and caffeine serum concentrations was found in neonates who had TDM of caffeine citrate therapy in the post-extubation period, whereas a significant association between tachycardia and concentrations existed. Notwithstanding the absence of severe adverse reactions, TDM should be considered in critically ill neonates with unexplained adverse effects, such as tachycardia. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40360-016-0065-x) contains supplementary material, which is available to authorized users.