Abstract
Introduction 45% of all medicines available in Switzerland are not authorised for use in children, and consequently off-label prescribing is common practice in paediatric care.2 In the absence of official dosing recommendations in drug labels, other strategies are needed to help professionals selecting the optimal dose for their paediatric patients. We present a three-step approach to provide safe off-label dosing recommendations for children on a national level.
Methodology Step 1: Along with the introduction of the paediatric regulation in Switzerland, an initiative was developed to harmonise dosing recommendations for off-label use, based on evidence from scientific literature combined with national expert knowledge from clinical practice.2 Step 2: When few data were available to harmonise dosing recommendations, real-world demographic data were consulted and/or data from daily clinical routine were gathered. An online platform was built to access and use these data for pharmacokinetic (PK) modelling and simulation. Step 3: In cases where standardised dosing was expected insufficient, a personalised approach was adopted, incorporating therapeutic monitoring (TDM) and pharmacogenetic (PGx) testing to individualise drug therapy.
Results A standardised harmonisation process was established and almost 600 off-label dosing recommendations for 170 active substances were published in the SwissPedDose database. For anti-infective drugs, where the harmonisation was challenging, dosing recommendations were optimised applying in silico simulation for amikacin based on real-world demographic data and PK modelling for gentamicin based on health-related personal data and TDM results from clinical practice using the recently built and secure online platform SwissPKcdw.3–5 This platform also allowed a PGx analysis to individualise voriconazole treatment in children suffering from invasive fungal infections.6
Conclusions Since Swiss drug labels are lacking paediatric dosing recommendations, more emphasis should be placed on improving the safety of off-label prescribing for children. Three steps, first harmonising the dosing recommendations, second applying modelling and simulation to provide a scientific rationale for optimising the recommendations, and third incorporating results of TDM and PGx tests for individualising drug therapy, allow to approach optimal drug dosing in children.
References
Tilen R, et al. Information in drug labels about use in children is limited and needs standardisation: a systematic analysis in Switzerland. Manuscript in preparation (submission to ArchDisChild planned in March).
Tilen R, et al. Development of the Swiss Database for dosing medicinal products in pediatrics. Eur J Pediatr 2022.
Gotta V, et al. Leveraging pharmacometric approaches to facilitate a national dose harmonization process in neonatology. Manuscript submitted. 2023.
Paioni P, et al. Gentamicin population pharmacokinetics in pediatric patients-A prospective study with data analysis using the Saemix package in R. Pharmaceutics 2021.
Goers R, et al. SwissPKcdw - A clinical data warehouse for the optimization of pediatric dosing regimens. CPT Pharmacometrics Syst Pharmacol 2021.
Tilen R, et al. Pharmacogenetic analysis of voriconazole treatment in children. Pharmaceutics. 2022.