Application of a physiologically‐based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate

Abstract

Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically-based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration-time curve, maximum concentration in plasma and time to maximum plasma concentration, within two-fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.

Identification and quantification of blood–brain barrier transporters in isolated rat brain microvessels

“…The development of PBPK models for psychoactive drugs (and other drugs that can penetrate the BBB), particularly when they are subject to active uptake or efflux, is therefore dependent on robust and reliable measurement of the abundances of BBB transporters in humans as well as animal species used in pre-clinical studies (Ball et al 2014;Gaohua et al 2016). Recent applications of such PBPK models also highlight their potential in assessing the needs of subpopulations, which are not fully explored in clinical studies (e.g., pediatrics, brain cancer patients) as reported previously (Spanakis et al 2016;Kalluri et al 2017;Donovan et al 2018).…”

Gut Reactions: Breaking Down Xenobiotic–Microbiome Interactions

“…There are also advantages to the use of in silico models to predict outcome from a variety of inputs, possibly by combining microbiota metabolism rates with host drug absorption and metabolic rates. Specifically adapting many of the emerging physiologically based pharmacokinetic models, which predict drug levels in tissues based on a variety of drug and host parameters (Min and Bae, 2017;Thiele et al, 2017;Donovan et al, 2018), to allow for greater contribution of microbiota-mediated metabolism, may be a useful approach to predict overall clinical impact.…”

Physiologically‐Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants

“…A model using pediatric methotrexate data included digitized CSF and brain extracellular fluid concentrations and found that, although the model accurately characterized methotrexate's CNS distribution in rats, dogs, and human adults, it underestimated CNS concentrations in critically ill children aged 2–17 years . An additional PBPK model of bumetanide was developed using adult plasma data and scaled to various pediatric populations . It accurately predicted plasma concentrations for all infants except critically ill neonates, and it did not evaluate the model's CNS distribution predictions with CSF samples .…”

“…An additional PBPK model of bumetanide was developed using adult plasma data and scaled to various pediatric populations . It accurately predicted plasma concentrations for all infants except critically ill neonates, and it did not evaluate the model's CNS distribution predictions with CSF samples . Our model was developed using numerous plasma samples from preterm and term infants, many from a preterm population receiving the drug prophylactically.…”