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Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia
Author(s) -
Bijleveld Yuma A.,
Haan Timo R.,
Lee Hanneke J. H.,
Groenendaal Floris,
Dijk Peter H.,
Heijst Arno,
Jonge Rogier C. J.,
Dijkman Koen P.,
Straaten Henrica L. M.,
Rijken Monique,
Zonnenberg Inge A.,
Cools Filip,
Zecic Alexandra,
Nuytemans Debbie H. G. M.,
Kaam Anton H.,
Mathot Ron A. A.
Publication year - 2016
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12883
Subject(s) - medicine , gentamicin , hypothermia , anesthesia , perinatal asphyxia , pharmacokinetics , nonmem , aminoglycoside , population , gestational age , regimen , dosing , asphyxia , surgery , pregnancy , antibiotics , biology , genetics , environmental health , microbiology and biotechnology
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 ® ) 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.