Tamara van Donge

Abstract Introduction: Large variability in neonatal amoxicillin dosing recommendations may reflect uncertainty about appropriate efficacy and toxicity targets. Objective: To model efficacious and safe exposure for current neonatal amoxicillin dosing regimens, given a range of assumptions for minimal inhibitory concentration (MIC), targeted % f T>MIC, and potential for aminopenicillin related neurotoxicity. Methods: Individual intravenous amoxicillin exposures based on six international and nine Swiss neonatal dosing recommendations, reflecting the range of current dosing approaches, were assessed by a previously developed population pharmacokinetic model informed by neonatal data from an international cohort. Exposure was simulated by attributing each dosing regimen to each patient cohort. Endpoints of interest were % f T>MIC and potential neurotoxicity using Cmax >140 mg/L as threshold. Results: None of the dosing regimens achieved targets of ≥100% f T>MIC at any of the relevant MICs for a desired probability of target attainment (PTA) of ≥90%. All regimens achieved a PTA≥90% for Streptococcus agalactiae (MIC 0.25mg/L) and Listeria monocytogenes (MIC 1mg/L) when targeting ≤70% f T>MIC. In contrast, none of the regimens resulted in a PTA≥90% targeting ≥70% f T>MIC for enterococci (MIC 4mg/L). The maximum amoxicillin concentration associated with potential neurotoxicity was exceeded using four dosing regimens (100 mg/kg q12, 60/30 mg/kg q12/8, 50 mg/kg q12/8/6 and 50 mg/ kg q12/8/4) for ≥10% of neonates. Conclusions: The acceptability of regimens is highly influenced by efficacy and toxicity targets, the selection of which is challenging. Novel randomised trial designs combined with pharmacometric modelling and simulation could assist in selecting optimal dosing regimens in this understudied population. Key words: amoxicillin, dosing regimen, neonates, PKPD targets, neurotoxicity, model- based simulations Abbreviations: maximum concentration (Cmax), gestational age (GA), Streptococcus agalactiae (GBS), minimal inhibitory concentration (MIC), pharmacokinetics (PK), pharmacokinetic/pharmacodynamic (PKPD), postnatal age (PNA), probability of target attainment (PTA), neonatal intensive care unit (NICU), World Health Organization (WHO)