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
AU - Brouwer, Mieke J.
AU - Van Den Broek, Marcel P.
AU - Rademaker, Carin M A
AU - Liem, Djien
AU - Steiner, Katerna
AU - Simons, Sinno H P
AU - Bos, Annelies A.
AU - Mulder-De Tollenaer, S. M.
AU - Groot Jebbink-Akkerman, L. J M
AU - Sonnaert, Michel
AU - Camfferman, Fleur Anne
PY - 2016/6
Y1 - 2016/6
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 patientsMETHODS: 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®) 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 (Vc) 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.
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 patientsMETHODS: 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®) 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 (Vc) 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.
KW - controlled hypothermia
KW - gentamicin
KW - neonates
KW - population pharmacokinetics
UR - https://www.scopus.com/pages/publications/84960157521
U2 - 10.1111/bcp.12883
DO - 10.1111/bcp.12883
M3 - Article
C2 - 26763684
AN - SCOPUS:84960157521
SN - 0306-5251
VL - 81
SP - 1067
EP - 1077
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 6
ER -