Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Abstract

Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children on ECMO, we developed a PBPK model, which was validated using fluconazole pharmacokinetic (PK) data in adults and critically ill infants. Next, an ECMO compartment was added to the PBPK model and parameterized using data from a previously published ex vivo study. Simulations using the final ECMO PBPK model reasonably characterized observed PK data in infants on ECMO, and the model was used to derive dosing in children on ECMO across the pediatric age spectrum. This approach can be generalized to other forms of extracorporeal life support (ECLS), such as dialysis.

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

“…Perfusion‐rate limitation was assumed with each compartment represented as well stirred. A previously developed fluconazole PBPK model was scaled from adults to preterm infants . Briefly, the adult base model, developed in PK‐Sim, assumed clearance occurred 85% renally and 15% hepatically via UGT2B7 mechanisms .…”

“…A previously developed fluconazole PBPK model was scaled from adults to preterm infants . Briefly, the adult base model, developed in PK‐Sim, assumed clearance occurred 85% renally and 15% hepatically via UGT2B7 mechanisms . Adult renal clearance via the glomerular filtration rate (GFR) was predicted using a GFR fraction to account for tubular reabsorption or secretion as defined by Eq.…”

“…where the empiric CL R is the literature renal clearance value in adults, and the expected CL R is the clearance as a result of GFR if there was no tubular reabsorption (i.e., fraction unbound × normal GFR) . A GFR fraction of less than one indicates tubular reabsorption, whereas a GFR fraction of greater than one indicates tubular secretion.…”

“…The preterm infant population from PK‐Sim was used to develop virtual infant populations. To examine if the infant cohort from these two studies was similar with respect to distribution and clearance to the cohort from the previously developed pediatric PBPK model, the dose‐normalized and time‐normalized prophylaxis study plasma data were used for the optimization of lipophilicity, UGT2B7 clearance, and GFR fraction using the Nelder–Mead algorithm . In addition, the PK‐Sim Standard, Rodgers and Rowland, Schmitt, Poulin and Thiel, and the Berezhkovskiy methods were evaluated for the calculation of partition coefficients and cellular permeability values.…”

“…The objective of this study was to develop a PBPK model of fluconazole in preterm and term infants that accurately predicts CSF concentrations to inform dosing for the treatment of HCME. This PBPK model was scaled to preterm and term infants from a previously developed PBPK model using plasma data from a study in preterm infants, henceforth referred to as the prophylaxis study, and then externally evaluated using plasma data from a second clinical study of preterm and term infants, henceforth referred to as the Pediatric Pharmacology Research Unit (PPRU) study . CSF concentration predictions were evaluated using CSF samples obtained from both studies, and the model was used to evaluate dosing guidelines.…”