TY - JOUR
T1 - Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia
AU - Bijleveld, Yuma A.
AU - de Haan, Timo R.
AU - van der Lee, Hanneke J. H.
AU - Groenendaal, Floris
AU - Dijk, Peter H.
AU - van Heijst, Arno
AU - de Jonge, Rogier C. J.
AU - Dijkman, Koen P.
AU - van Straaten, Henrica L. M.
AU - Rijken, Monique
AU - Zonnenberg, Inge A.
AU - Cools, Filip
AU - Zecic, Alexandra
AU - Nuytemans, Debbie H. G. M.
AU - van Kaam, Anton H.
AU - Mathot, Ron A. A.
PY - 2016
Y1 - 2016
N2 - AIM(S) Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic-ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients. METHODS Demographic, 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 (R)) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS A 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(-1) h(-1) (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (V-c) was 0.46 l kg(-1) (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS This 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(-1) 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
AB - AIM(S) Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic-ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients. METHODS Demographic, 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 (R)) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS A 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(-1) h(-1) (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (V-c) was 0.46 l kg(-1) (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS This 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(-1) 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
U2 - https://doi.org/10.1111/bcp.12883
DO - https://doi.org/10.1111/bcp.12883
M3 - Article
C2 - 26763684
SN - 0306-5251
VL - 81
SP - 1067
EP - 1077
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
IS - 6
ER -