Abstract
BACKGROUND: Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies.METHODS: A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5mg/kg intravenous (i.v.) load then 1.8mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10mg/L) associated with clinical response was examined.RESULTS: Birth weight was a significant predictor of theophylline clearance and volume of distribution (p<0.05). The median half-life was 39.5h (range 27.2-50.4). An aminophylline loading dose of 7mg/kg followed by 1.6mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates.CONCLUSIONS: In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population.IMPACT: Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known.Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE.As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.Fig. 1INDIVIDUAL PREDICTED THEOPHYLLINE CONCENTRATIONS IN NEONATES WITH HIE RECEIVING HYPOTHERMIA BASED ON THE FINAL PHARMACOKINETIC MODEL AS COMPARED TO THE OBSERVED MEASURED CONCENTRATIONS.: DBS dried blood samples measured as part of a prospective study, plasma samples measured as part of clinical care.Fig. 2Relationship between the average theophylline concentration over the first 24h of treatment (Cavg,24) and (a) change in urine output (?UOP) 24h after the start of treatment and (b) change in serum creatinine (?SCr) 48h after the start of treatment.Fig. 3Predicted theophylline concentration-time course after aminophylline using (a) dosing strategy used in clinical care during the study time period (loading dose 5mg/kg, followed by 1.8mg/kg every 6h) and (b) optimized dosing strategy (loading dose 7mg/kg, followed by 1.6mg/kg every 12h). Each dosing strategy was simulated in 3000 neonates using the final population pharmacokinetic model. Solid line represents the median and dashed lines represent the 10th and 90th percentile. Shaded area represents targeted concentration range of 4-10mg/L.
View details for DOI 10.1038/s41390-020-01140-8
View details for PubMedID 32919393