Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia

Abstract

Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxicÀischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients. METHODSDemographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the 'PharmaCool Study') were collected. A non-linear mixed-effects regression analysis (NONMEM ® ) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTSA total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg À1 h À1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (V c ) was 0.46 l kg À1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONSThis study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg À1 every 36 h or every 24 h for patients with GA 36-40 weeks and GA 42 weeks, respectively. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Little is known of the pharmacokinetic (PK) properties of gentamicin in neonates receiving controlled hypothermia. Only a few retrospective studies have been performed to evaluate these properties. For example, conflicting data exist with regard to the changes in clearance (CL) of gentamicin in this population. WHAT THIS STUDY ADDS• A description of the PK properties of gentamicin in this patient population based on prospectively gathered data was obtained.• We found a 29% higher CL during normothermia compared with the hypothermic and rewarming periods.• We suggest a new dosing regimen with which adequate peak and trough levels will be acquired.

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

“…26 Furthermore, in a previous study we found that cooling delayed normalization of gentamicin Cl, an antibiotic also mainly eliminated by glomerular filtration. 27 For Vc no significant covariate-parameters relationship was identified besides BW. In our patient population the Vc was 0.34 L/kg (IIV of 114.6%) for a typical patient (GA 40 weeks, BW 3,000 g).…”

Population Pharmacokinetics of Gentamicin in Neonates with Hypoxemic‐Ischemic Encephalopathy Receiving Controlled Hypothermia

“…The covariates found to be statistically significant and subsequently included in the final population pharmacokinetic model process were mildly different between the first study cited here and this investigation. The former found GA and BW as covariates on CL, whereas our data demonstrated BW as a covariate on Vd . Physiologically and pharmacokinetically, each of the covariates included between the two studies are appropriate, and differences in the patient population between the study sites such as urine output, fluid status, and the amounts of inotropes required could explain why one model was enhanced with GA and BW for CL as opposed to BW for Vd.…”

“…The number of samples obtained during the active cooling phase for gentamicin concentration determination between the two studies was very similar. When comparing the pharmacokinetic parameters, the Vc between the two studies was similar, 0.45 L/kg and 0.44 L/kg, respectively, as was the estimation for the total Vd parameter of 0.86 L/kg and 0.96 L/kg, respectively . However, the CL values between the two investigations were notably different with an estimate of 1 ml/minute/kg versus 2.2 ml/minute/kg, respectively .…”

“…In 2016, one group performed a prospective pharmacokinetic study to assess the pharmacokinetics of gentamicin in neonates with HIE receiving CH . Similar to the data presented here, a two‐compartment model was found to best describe the respective pharmacokinetic data.…”

“…Previous data on the effects of CH on the pharmacokinetics and pharmacodynamics of gentamicin during the active cooling phase are not only conflicting but were also obtained retrospectively with a limited pharmacokinetic sampling strategy . To date, there is a single prospective analysis of the pharmacokinetics of gentamicin in term neonates with HIE receiving CH . Therefore, the purpose of this investigation was to characterize the population pharmacokinetics and pharmacodynamic target attainment of gentamicin in neonates with HIE receiving CH to provide additional data and guidance on appropriate initial gentamicin dosing recommendations in this patient population compared with non‐HIE neonates.…”