Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia

Adam Frymoyer, Krisa P Van Meurs, David R Drover, Jelena Klawitter, Uwe Christians, Valerie Y Chock, Adam Frymoyer, Krisa P Van Meurs, David R Drover, Jelena Klawitter, Uwe Christians, Valerie Y Chock

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 (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/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 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/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.

Figures

Figure 1.
Figure 1.
Individual 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 prospective study; Plasma, plasma samples measured as part of clinical care.
Figure 2.
Figure 2.
Relationship between the average theophylline concentration over the first 24 hours of treatment (Cavg,24) and a) change in urine output (ΔUOP) 24 hours after start of treatment and b) change in serum creatinine (ΔSCr) 48 hours after start of treatment.
Figure 3.
Figure 3.
Predicted theophylline concentration-time course after aminophylline using a) dosing strategy used in clinical care during the study time period (loading dose 5 mg/kg followed by 1.8 mg/kg every 6 hours) and b) optimized dosing strategy (loading dose 7 mg/kg followed by 1.6 mg/kg every 12 hours). 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 to 10 mg/L.

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