LB-012 - ETHANOL AS AN EXCIPIENT IN DRUG FORMULATIONS ADMINISTERED TO NEONATES: PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING TO INFORM SAFETY.

J. Freriksen¹, M. de Hoop-Sommen¹, H. Mulla^2,3, M. Turner^4,5,6, R. Pang⁷, N. Robertson^7,8, J. Standing⁹, S. de Wildt^10,11; ¹Radboud University Medical Center, Nijmegen, The Netherlands, ²University Hospitals of Leicester NHS Trust, Leicester, United Kingdom, ³Great Ormond Street Hospital for Children, London, United Kingdom, ⁴Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom, ⁵University of Liverpool, Liverpool, United Kingdom, ⁶Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom, ⁷University College London, London, United Kingdom, ⁸University of Edinburgh, Edinburgh, United Kingdom, ⁹UCL Great Ormond Street Institute of Child Health, London, United Kingdom, ¹⁰Radboud Institute for Health Sciences, Nijmegen, The Netherlands, ¹¹Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: For many years, ethanol has been used as an excipient in neonatal drug formulations. Its pharmacokinetics (PK) have not been well characterized; proposed safety levels are not evidence-based and differ substantially (maximum blood level: 1 mg/dL vs. 25 mg/dL) with a proposed maximum single dose of 6 mg/kg. While physiologically-based pharmacokinetic (PBPK) modeling is yet mainly employed to study PK of pharmaceuticals, it can be an attractive tool to assess exposure to excipients as well and thereby increase the evidence base supporting safe use.

Methods: The PBPK modeling platform Simcyp® v21 and published input parameters were used to predict ethanol PK. The availability of adult and neonatal PK data enabled evaluation of the predictive performance of the model. Subsequently, prospective simulations of ethanol exposure in neonates were conducted. Maximum safe intravenous (IV) doses were identified, taking into account the proposed safety levels.

Results: Model performance was considered acceptable, despite an underprediction of exposure in all age groups. Therefore, a safety margin of two-fold was applied. A maximum IV dose of 6 mg/kg seems appropriate, taking into consideration the 1 mg/dL safety level. Modelling results suggest that much higher doses (up to 110 mg/kg as an IV single dose) can be considered safe when taking into consideration the 25 mg/dL safety level.

Conclusion: This proof-of-concept study showed that neonatal exposure to ethanol can be predicted in silico. Knowledge of the models’ predictive performance – which can be derived from verification simulations with in vivo PK data – is essential to ensure model credibility and to justify a safety margin around a model-informed dose. In this case, a two-fold safety margin was applied and maximum dosing strategies were proposed.