Pharmacometric approach to assist dosage regimen design in neonates undergoing therapeutic hypothermia

BACKGROUND: Therapeutic hypothermia (TH) is the treatment of choice for neonates diagnosed with perinatal asphyxia (PA). Dosing recommendations of various therapeutic agents including antimicrobials were not specifically available for the neonates undergoing TH. METHODS: A systematic search methodology was used to identify pharmacokinetic (PK) studies of antimicrobials during TH. Antimicrobials with multiple PK studies were identified to create a generalizable PK model. Pharmacometric simulations were performed using the PUMAS software platform to reproduce the results of published studies. A suitable model that could reproduce the results of all other published studies was identified. With the help of a generalizable model, an optimal dosage regimen was designed considering the important covariates of the identified model. RESULTS: With the systematic search, only gentamicin had multiple PK reports during TH. A generalizable model was identified and the model predictions could match the reported/observed concentrations of publications. Birth weight and serum creatinine were the significant covariates influencing the PK of gentamicin in neonates. A dosage nomogram was designed using pharmacometric simulations to maintain gentamicin concentrations below 10 μg/mL at peak and below 2 μg/mL at trough. CONCLUSIONS: A generalizable PK model for gentamicin during TH in neonates was identified. Using the model, a dosing nomogram for gentamicin was designed. IMPACT: Dosing guidelines for antimicrobials during TH in neonates is lacking. This is the first study to identify the generalizable model for gentamicin during TH in neonates. Nomogram, proposed in the study, will aid the clinicians to individualize gentamicin dosing regimen for neonates considering the birth weight and serum creatinine.