Pharmacokinetics of Cefepime in children receiving continuous renal replacement therapy
Adam Bensimhon, MD
BACKGROUND: Continuous renal replacement therapy (CRRT) is life saving for children with acute kidney injury (AKI); however, despite technological and clinical advances in CRRT over the past two decades, mortality rates in children receiving CRRT still exceed 40%. The high mortality rates in children on CRRT are suspected to be, in part, a result of significantly altered drug disposition by the extracorporeal CRRT circuit, resulting in suboptimal antibiotic dosing. Currently, no dosing recommendations exist for children on CRRT.
GAP: This study will close an important knowledge gap in pediatric nephrology and critical care by establishing dosing recommendations for cefepime in children with AKI on CRRT.
HYPOTHESIS: We hypothesize that CRRT circuit adsorption will result in significant loss of cefepime. In addition, we hypothesize that physiologically based pharmacokinetic (PBPK) models will predict drug exposure of cefepime in critically ill children, and can be adapted to different physiologic states, including renal dysfunction and CRRT support. Lastly, we hypothesize that addition of the CRRT circuit into a PBPK model will predict drug exposure of cefepime in 90% of children on CRRT.
METHODS: We will evaluate the impact of the CRRT circuit on cefepime disposition in isolation through ex vivo studies. We will then build PBPK models and use the ex vivo data to parameterize a CRRT compartment. Lastly, we will evaluate model predictions using prospective, opportunistic PK samples of cefepime from children receiving CRRT.
IMPACT: The validated model will be used to determine optimal dosing of cefepime in children on CRRT, as well as serve as a platform to determine dosing for other commonly used drugs in children on CRRT.