Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia.

Abstract

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 (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.

• Authors: Yuma A Bijleveld, Timo R de Haan, Hanneke J H van der Lee, Floris Groenendaal, Peter H Dijk, Arno van Heijst, Rogier C J de Jonge, Koen P Dijkman, Henrica L M van Straaten, Monique Rijken, Inge A Zonnenberg, Filip Cools, Alexandra Zecic, Debbie H G M Nuytemans, Anton H van Kaam, Ron A A Mathot, PharmaCool study group
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 81 Issue 6 Pg. 1067-77 (06 2016) ISSN: 1365-2125 [Electronic] England
• PMID: 26763684 (Publication Type: Journal Article, Multicenter Study, Observational Study, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Gentamicins

Topics

• Anti-Bacterial Agents (pharmacokinetics)
• Cohort Studies
• Computer Simulation
• Female
• Fetal Hypoxia
• Gentamicins (pharmacokinetics)
• Gestational Age
• Humans
• Hypothermia, Induced
• Hypoxia-Ischemia, Brain (drug therapy)
• Infant, Newborn
• Male
• Models, Statistical
• Prospective Studies
• Rewarming