The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N 5 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW 3,000 g, 2 days PNA (i.e., TEMP 33.58C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.08C. The respective contributions of both covariates were 23% and 27%. Based on Monte Carlo simulations we recommend 50 and 75 mg/kg/24h amoxicillin in three doses for patients with GA 36-37 and 38-42 weeks, respectively. Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? þ To date, there are no data on the effect of moderate hypothermia on the pharmacokinetics (PK) of amoxicillin in term neonates. Only few studies have been performed to evaluate the PK of this antibiotic in noncooled (pre)term neonates. WHAT QUESTION DID THIS STUDY ADDRESS? þ To our knowledge, this is the first prospective study evaluating and describing the PK of amoxicillin during all phases of controlled hypothermia in newborns, e.g., the hypothermic, rewarming, and normothermic phases.WHAT THIS STUDY ADDS TO OUR KNOWLEDGE þ A description of the PK properties of amoxicillin in term newborns with hypoxic-ischemic encephalopathy (HIE) due to perinatal asphyxia receiving hypothermia treatment. Gestational age (GA), postnatal age (PNA), urine output, and body temperature were significant covariates on amoxicillin clearance (Cl). HOW THIS MIGHT CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE þ Based on the newly developed PK-model, we advise an amoxicillin dosing regimen of 50 or 75 mg/kg/24h in three doses for patients with GA 36 or GA 38-42 weeks, respectively.Term neonates who experience a severe hypoxic-ischemic insult during birth and develop encephalopathy are treated with hypothermia.1,2 This improves long-term outcomes and reduces mortality rates.2-9 These patients may suffer from early-onset sepsis with Streptococcus agalactiae (incidence rate 0.43% (95% confidence interval (CI) 0.37-0.49)), while Listeria monocytogenes should also be considered.10 Because asphyxia due to infection is difficult to distinguish from asphyxia without infection, antibiotics, such as amoxicillin, are frequently used.11 For efficacy, as a surrogate marker, the time that the nonprotein-bound concentration in blood exceeds the minimum inhibitory concentration (T>MIC) should be at least 40-50% in these patients.12 Although b-lactam antibiotics such as amoxicillin are considered safe due to the wide therapeutic range, excessive accumulation can lead to the development of adverse drug events, such as seizures and crystalluria. 13Despi...