Fuchs Aline (1), Gotta Verena (1), Johannes Van Den Anker (1,2,3), Marc Pfister (1)
(1) Division of Paediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland, (2) Intensive Care and Department of Surgery, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, the Netherlands, (3) Division of Clinical Pharmacology, Children’s National Health System, Washington, DC, USA
Objective: To provide a simple gentamicin dosing regimen recommendation for outpatient treatment of neonates and young infants (0 – 59 days old) with possible serious bacterial infection when referral is not an option. The simple dosing regimen should be based on three body weight bands allowing effective and safe exposure in a majority of these infants.
Methods: Target peak concentrations of gentamicin relative to the minimum inhibitory concentration (MIC) was set to > 5 assuming a MIC value of 0.5 mg/L, whereas target trough concentrations was set to < 2 mg/L to maximize efficacy while mitigating the risk of drug related nephro- and oto-toxicity. The following dosing scenarios were evaluated: doses ranging from 8 to 14 mg, 14 to 20 mg and 20 to 26 mg based on three weight groups ([1.5 – 2.4], [2.5 – 3.9], [4 – 6] kg) respectively, administered every 24, 36, and 48 hours. Gentamicin exposure was evaluated by simulation after the first intramuscular (IM) dose and after seven consecutive IM doses utilizing a published pharmacokinetic model1. The simulated population of neonates and infants comprised 450 virtual neonates with realistic combinations of weight (1.5 kg to 6.0 kg) and postnatal age (0 to 59 days) based on WHO growth charts. Each of these 450 patients was simulated 100 times to account for both inter- and intra-individual variability.
Results: Given predefined target peak and trough concentrations, simulations indicated that doses of 8, 16 and 24 mg every 24 hours bring > 80% of patients in the desired target ranges for 1.5 – 2.4 kg, 2.5 – 3.9 kg and 4.0 – 6.0 kg weight bands, respectively. After seven doses administered every 24 hours, no obvious accumulation of gentamicin was found, likely due to post-natal, time dependent maturation resulting in an increase in drug clearance. If a peak concentration of 8 mg/L is considered, the 1.5 – 2.4 kg would require doses of 10 mg to reach an appropriate peak concentration in 80% of patients. It would result in 17% of infants with a trough concentration > 2mg/L over a 24h dosing interval.
Conclusion: Based on pharmacokinetic simulations, doses of 8, 16 and 24 mg every 24 hours for the 1.5 – 2.4 kg, 2.5 – 3.9 kg and 4 – 6 kg weight bands respectively, are expected to be appropriate for most patients in this context. This simplified scheme of administration assumes that a peak concentration of 5 mg/L and a trough concentration < 2 mg/L are effective and safe respectively.
Reference:
[1] Thomson AH, Kokwaro GA, Muchohi SN et al. Population pharmacokinetics of intramuscular gentamicin administered to young infants with suspected severe sepsis in Kenya. Br J Clin Pharmacol. 2003 Jul;56(1):25-31.
Reference: PAGE 25 (2016) Abstr 5910 [www.page-meeting.org/?abstract=5910]
Poster: Drug/Disease modeling - Paediatrics