Physiologically-based Pharmacokinetics in Critically Ill Children

Abstract

Extracorporeal membrane oxygenation (ECMO) is used to support cardiorespiratory failure in critically ill infants, children, and adults. In these vulnerable populations, the effect of ECMO on drug disposition leaves clinicians with uncertainty about dosing. The goal of this dissertation research was to develop a physiologically-based pharmacokinetic (PBPK) modeling approach that translated results from ex vivo ECMO studies to bedside dosing recommendations. To determine optimal dosing, the impact of the ECMO circuit on antifungal disposition was first assessed in isolation through ex vivo studies of three antifungal drugs. These experiments showed variable degrees of extraction by the ECMO circuit with micafungin highly extracted and fluconazole and amphotericin B deoxycholate with limited extraction. These results were then used to parameterize drug-specific ECMO compartments in the PBPK models. Model building followed an established workflow whereby a PBPK model was developed in adults and scaled to children. Once the Pediatric PBPK Model met acceptance criteria, an ECMO compartment was added to the Pediatric PBPK Model to form the ECMO PBPK Model. The fluconazole ECMO PBPK Model over-predicted exposure (1.13 fold error) but was within the pre-specified acceptance criteria of 0.7-1.3 fold error. PBPK-predicted dosing recommendations showed good agreement with recommendations based on the Fluconazole ECMO PK Trial. The micafungin ECMO PBPK Model also over-predicted exposure (1.16 fold error), but, again, dosing recommendations were in close agreement with recommendations determined from the trial. The two clinical PK trials of fluconazole and micafungin in children on ECMO were performed in parallel with the PBPK model building. Both the Fluconazole and Micafungin ECMO PK Trials showed that exposure was significantly lower in children on ECMO compared to children not on ECMO. Although determining optimal dosing for these two commonly used drugs in children on ECMO was important, more importantly, the PBPK modeling developed in this dissertation demonstrated the utility of this approach to understand and quantify the physiologic alterations driving drug disposition in critically ill children. A more precise, refined, integrated approach for drug dosing in this pediatric sub-population will improve both the safety and efficacy of drug therapy in children supported with ECMO.Doctor of Philosoph