Pharmacokinetics and Safety of Caffeine in Infants with Hypoxic-Ischemic Encephalopathy
Wesley Jackson, MD, MPH
BACKGROUND: Therapeutic hypothermia has improved mortality and morbidity in infants with hypoxic-ischemic encephalopathy (HIE). However, death and neurodevelopmental impairment resulting from HIE remain high and there is an urgent, unmet need for adjuvant therapies.
GAP: This study will characterize the pharmacokinetics (PK) and safety of caffeine in the setting of HIE and therapeutic hypothermia and evaluate its preliminary effectiveness in offering neuroprotection for infants with HIE.
HYPOTHESIS: Caffeine clearance will be ≥ 20% lower than expected for gestational age and birth weight. The frequency of seizures in both treatment cohorts will be within 20% of published results of infants treated with therapeutic hypothermia in the NICHD trial. The risk ratio for an abnormal MRI prior to discharge will be between 0.7 and 1.1 in treated infants compared to published results of infants treated with therapeutic hypothermia in the NICHD trial.
METHODS: We will perform a phase I, open-label, single-center trial designed to characterize the PK and safety of two dosing regimens of caffeine in infants undergoing therapeutic hypothermia for HIE. This trial will include infants at least 36 weeks gestational age undergoing therapeutic hypothermia for moderate to severe HIE and enrolled in the first 12 hours of life.
IMPACT: This study will provide the necessary first step to design next phase trial to evaluate the preliminary effectiveness of caffeine in reducing brain injury in infants with HIE.