Minimization of a utility function for optimizing the dosing frequency of amoxicillin administration in neonates according to a fixed PK/PD index
Aline Fuchs (1), Julia Bielicki (1,2), Andrew Atkinson (1,3), Johannes Van Den Anker (1,4,5), Marc Pfister (1)
(1) Paediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland (2) Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom (3) Department of Infectious Diseases, University Hospital Bern, Bern, Switzerland (4) Intensive Care and Department of Surgery, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, the Netherlands (5) Division of Clinical Pharmacology, Children’s National Health System, Washington, DC, USA
Objective: To optimize a priori amoxicillin dosing individualization in neonates according to demographic characteristic (covariate) cut-offs by achieving antibiotic exposure to concentrations above the minimum inhibitory concentration (MIC) during the entire dosing interval (100%T>MIC), while avoiding drug administered in excess or prolonged time below the MIC.
Methods: The approach uses a data-derived model and minimization of a utility function to identify optimal dosing strategies. The utility function implemented in NONMEM allows quantification of (i) the risk associated with the deviation from the treatment target (100%T>MIC) i.e. aiming to achieve drug concentrations for 100%T>MIC (efficacy), and to minimize the time neonates are exposed to concentrations below the MIC (risk of regrowth), and (ii) the amount administered in excess (risk of adverse events)1. The non-species related breakpoint for amoxicillin resistance of 8 mg/L was used for the MIC2. Single administered dose was fixed, dosing interval and covariate cut-off were the parameters to be optimized
Results: For a fixed dose of 50 mg/kg, up to 3 dosing categories were investigated, optimum weight cut-offs were 3 kg for 2 categories, and 1.5 and 3 kg for 3 categories. However, the difference in estimated dosing interval per weight subgroup was small: for 2 dosing categories, the dosing intervals were 16.4h (<3kg) and 15.3h (> 3kg); for 3 dosing categories, they were 18.5h (1.5 and <3kg) and 15.8h (>3 kg) for first dose of treatment, respectively. This suggests that amoxicillin exposure might be optimal without neonatal dosing categories based on weight cut-offs when using 50 mg/kg as a fixed dose. For clinicians and driven by efficacy endpoints, a 12h interval appears to be the most convenient. In terms of efficacy, 50 mg/kg every 12h leads to 93% of patients being above 100%T>MIC and 1.5% being > 4h below the MIC after the first dose.
Conclusions: The method illustrates a weighted-quantitative drug dosing decision based on a combined utility function. This is particularly valuable in the dynamic neonatal population which exhibits highly correlated weight and age values. Further investigations are required with regards to the choice of the most appropriate demographic factor(s) readily implementable during routine clinical care that can be used for a priori dosing individualization in this fragile population. The unpublished population PK model used here requires validation.
References:
[1] Viberg A, Cars O, Karlsson MO, Jönsson S. Estimation of cefuroxime dosage using pharmacodynamic targets, MIC distributions, and minimization of a risk function. J Clin Pharmacol. 2008 Nov;48(11):1270-81
[2] EUCAST. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_7.0_Breakpoint_Tables.pdf. (2017-02-20)
