Journal
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
Volume 7, Issue 10, Pages 629-637Publisher
WILEY
DOI: 10.1002/psp4.12338
Keywords
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Categories
Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [1K23HD075891, 2K24HD058735]
- National Institutes of Health (NIH) [1R01-HD076676-01A1]
- National Center for Advancing Translational Sciences of the NIH [UL1TR001117]
- National Institute of Allergy and Infectious Disease (NIAID) [HHSN272201500006I, HHSN272201300017I]
- NICHD [HHSN275201000003I]
- Biomedical Advanced Research and Development Authority (BARDA) [HHSO100201300009C]
- non-profit organization Thrasher Research Fund
- NIH from the National Institute of General Medical Sciences [R01 GM041935, R35 GM122576]
- NIH [1K23HD075891, 1R01HD076676-01A1]
- Pediatric Critical Care and Trauma Scientist Development Program [5K12HD047349]
- industry for drug development in adults and children
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [K24HD058735, R01HD076676, K12HD047349, K23HD075891] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001117] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R35GM122576, R01GM041935] Funding Source: NIH RePORTER
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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.
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