Amikacin pharmacokinetics to optimize dosing in neonates with perinatal asphyxia treated with hypothermia [PublishAheadOfPrint]

Aminoglycosides pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed to treat neonates with (suspected) septicemia, however, none provide adjustments in the case of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations.

Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published dataset, we assessed the impact of PATH on amikacin PK using population modelling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines.

Amikacin clearance was decreased by 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that, increasing the dosing interval with 12 hours results in a decrease in percentage of neonates reaching toxic trough levels (> 5 mg/L) from 40—76% to 14—25%, while still reaching efficacy targets, compared to current dosing regimens.

Based on this study, a 12-hour increase in amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required as their clearance may also be impaired.

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