PBPK model-based extrapolation from adults to children to predict furosemide oral solution bioavailability
Cristian Valiante1, Fatima-zahra Agrad1, Esther Encinas1, Paula Muņiz1, Helen Shaw1, Monica Rodriguez1
(1) Model Informed Development. CTI Laboratory Services, Spain (2) Proveca Ltd., United Kingdom
Introduction
Furosemide is a loop diuretic that has been used in adults and children for decades, mainly for the treatment of heart failure, arterial hypertension and other pathologies that require reducing cardiac preload [1,2]. In paediatrics, furosemide is recognized as one of the most effective diuretics with fewer adverse effects in clinical practice [3]. Even today, relevant scientific information on the oral absorption of furosemide in the paediatric population is scarce and there is a significant lack of pharmacokinetic models that allow predicting its bioavailability from oral formulations intended for use in paediatrics, such as oral solutions and orodispersible tablets.
Objectives:
The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) model that allows predicting the bioavailability of an oral solution of furosemide in the different age groups within the paediatric population: neonates (1-28 days), infants and toddlers (from 1 month to less than 2 years), preschool children (from 2 to less than 6 years), school age children (from 6 to less than 12 years) and adolescents (from 12 to less than 18 years).
Methods: The PBPK model was developed and verified using PK-Sim® (Open Systems Pharmacology) software [4]. In the construction process, a previously published PBPK model of furosemide in adults [5] was used as a basis and extrapolation to paediatrics was made considering the demographic and physiological characteristics of the different age subgroups. For each of these age subsets, a virtual population (n = 500) was created, considering the concerned ages, body weights and body mass index. The model was validated using paediatric pharmacokinetic data following intravenous (IV) and oral administration of furosemide from scientific literature [6,7]. A prediction of AUC and/or Cmax with a relative bias of less than 30% was established as acceptance criteria. By applying the model, the plasma profiles of furosemide following administration of a single dose of 0.6 mg/kg both as an IV bolus and in the form of an oral solution were simulated in each one of the virtual population subgroups. The corresponding AUC for each route of administration and the bioavailability of the furosemide oral solution were then calculated and compared between subsets
Results:
The disposition model was developed considering the differential binding to plasmatic proteins between the paediatric population and adults, the metabolism by the UGT1A9 enzyme and the Michaelis-Menten kinetics of the OAT3 and MRP4 transporters previously optimized by Britz et al. (2020) [5] and the reference concentrations were optimized according to the scaling by age and weight. The disposition model adequately predicts the pharmacokinetics of furosemide in paediatrics, obtaining AUC values with a relative error of less than 20% compared to literature data [7]. Calculated bioavailability values ??for furosemide oral solution range from 0.68 (95%CI: 0.64 – 0.72) for neonates to 0.60 (95%CI: 0.57 – 0.64) in adolescents. In all cases, mean bioavailability did not deviate significantly from previously reported values ??for adults of approximately 0.64 and 0.60 for furosemide oral solution and tablets, respectively [8,9]. Even if a very small increase in the bioavailability of the oral solution was observed in the lower age subgroups compared to adults (geometric mean percentage difference was lower than 8.0%), this is not considered relevant taking into account the high variability of the metric reported in the literature [8,10,11].
Conclusions:
The developed PBPK model adequately predicts the pharmacokinetics of furosemide in paediatrics and is presented as an acceptable alternative tool to evaluate potential age dependencies on the bioavailability of a paediatric oral formulation of furosemide. According to our model, no significant differences in the bioavailability of furosemide are expected between adults and paediatrics of the different age groups, based on the PBPK model-based predictions.
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