Abstracts

Rationale: Approximately 30,000 newborns in the United States are born with congenital heart defects (CHD) each year, of whom a third require neonatal heart surgery using cardiopulmonary bypass (CPB) with or without deep hypothermic circulatory arrest (DHCA). Models of rat pup hypoxic-ischemic brain injury demonstrate substantial neuroprotection by topiramate after an intraperitoneal dose of 30 mg/kg, which attained a plasma concentration of approximately 25 μg/mL. The objective of this work was to develop a population pharmacokinetic (PK) model using data from intravenous (IV) topiramate experiments in newborn pigs to characterize topiramate disposition in response to CPB/DHCA. The final model was then applied as a simulation tool to investigate various dosing regimens that would achieve and maintain a target 25 μg/mL plasma concentration throughout CPB/DHCA. Methods: An initial model was constructed for plasma concentrations from 16 piglets administered 5 or 40 mg/kg IV topiramate. Simulations were performed using this model to identify a topiramate dose yielding a mean plasma concentration of 25 μg/mL at the end of a 15 minute infusion. The proposed dose was then administered to 6 piglets that underwent CPB/DHCA. Data from both studies were combined, and another model developed to describe the effects of CPB/DHCA on topiramate PK. Simulation studies were conducted to identify a dosing regimen that maintained the target concentration throughout CPB/DHCA. Results: Topiramate PK was initially described with a two-compartment model. Simulations suggested that a 20 mg/kg infusion over 15 minutes would yield the target concentration. Results from six piglets with CPB/DHCA confirmed that 20 mg/kg was sufficient to reach the target concentration but topiramate concentrations significantly fell once CPB was initiated, presumably due to the additional bypass circuit volume and circuit binding. The average concentration of 12.0 + 2.58 μg/mL remained stable throughout CPB for approximately 2 hours. The model was expanded to include a bypass compartment and minimal topiramate clearance (CL) during DHCA. The population initial CL was estimated to be 39.4 mL/min/kg. Simulations from the expanded model identified a topiramate dosing regimen of: (i) 20 mg/kg bolus over 15 minutes, followed by (ii) a 2.5 mg/kg/h infusion until the start of CPB, then (iii) a 10 mg/kg bolus would maintain the concentration through the end of CPB. An additional study in 5 piglets with CPB/DHCA confirmed the dosing regimen. The mean topiramate plasma concentration at two hours following CPB initiation was 27.6 + 2.44 μg/mL. Conclusions: Simulation studies using the final topiramate population PK model identified a dosing regimen that achieved and maintained a plasma concentration of 25 μg/mL throughout CPB/DHCA. This understanding of CPB/DHCA effects on topiramate PK will be directly applied to the pharmacological management of human newborns who require newborn heart surgery in a randomized neuroprotection trial.