Pyry Välitalo (1), John N. van den Anker (2), Karel Allegaert (3), Roosmarijn de Cock (1), Meindert Danhof (1), Catherijne A.J. Knibbe (1)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands, (2) Division of Paediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA, (3) Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Objectives: Recently, a neonatal pharmacokinetic model for amikacin has been published upon which a novel model-based dosing regimen was proposed [1]. As the amikacin covariate model was able to predict clearance of other renally cleared antibiotics such as gentamicin and tobramycin [2], the purpose of this study was to evaluate the performance of currently used gentamicin and tobramycin dosing guidelines for neonates in terms of achievement of recommended peak (5-12mg/L) and trough (<0.5mg/L) concentrations.
Methods: The recently published pharmacokinetic model for gentamicin and tobramycin [2] was used for deterministic and Monte Carlo simulations in neonates treated up to one week using NONMEM VII. The performance of existing dosing guidelines (the Dutch Children’s Formulary, the British National Formulary for Children, the Red Book, Neofax and Neonatal Formulary) was evaluated. Furthermore, a new dosing protocol was proposed.
Results: In the deterministic simulations with representative patients, most dosing guidelines resulted in trough concentrations above 0.5mg/L which is associated with increased renal toxicity. Monte Carlo simulations of existing dosing guidelines showed gentamicin peak and trough concentrations exceeding the recommended range more often than tobramycin concentrations. For the model-based dosing guideline, a uniform weight-scaled dose was found to lead to optimal peak concentrations, while the dosing interval to reach target trough concentrations was determined based on postnatal age and birth bodyweight.
Conclusions: Existing neonatal dosing guidelines for gentamicin and tobramycin are suboptimal across the heterogeneous population of preterm and term neonates. The proposed dosing guideline, which is based on birth bodyweight and postnatal age, performs well in terms of achieving the target concentrations.
References:
[1] De Cock RFW, Allegaert K, Schreuder MF, Sherwin CMT, de Hoog M, van den Anker JN, Danhof M, Knibbe CAJ. Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance. Clin Pharmacokinet. 2012;51(2):105–17
[2] De Cock RFW, Allegaert K, Sherwin CMT, Nielsen EI, de Hoog M, van den Anker JN, Danhof M, Knibbe CAJ. A Neonatal Amikacin Covariate Model Can Be Used to Predict Ontogeny of Other Drugs Eliminated Through Glomerular Filtration in Neonates. Pharm Res. 2014;31(3):754-67.
Reference: PAGE 23 (2014) Abstr 3117 [www.page-meeting.org/?abstract=3117]
Poster: Drug/Disease modeling - Paediatrics