Clearance of Amlodipine, Fentanyl, Fluconazole, Methylprednisolone, and Midazolam by Continuous Renal Replacement Circuits

Critically ill pediatric patients on continuous renal replacement therapy (CRRT) have high mortality rates ranging from 30% to 70%, due in part to altered drug exposure from drug-CRRT circuit interactions. Drug loss within CRRT circuits can occur through both clearance by the hemofilter and adsorption to circuit components. Although these interactions are known to exist, their impact on the pharmacokinetics of most drugs is unknown, resulting in limited drug dosing guidance and increased risk for suboptimal drug exposure. In this study, we administered amlodipine, fentanyl, fluconazole, methylprednisolone, and midazolam individually and in combination with ex vivo , closed-loop, blood-primed CRRT circuits to quantify drug-circuit interactions. Circuits were dosed to drug-specific therapeutic concentrations, and drug concentrations in both plasma and effluent were measured over time. For all drugs administered individually, variable extraction by the CRRT circuit was observed (mean plasma recovery 0.4-49%). For drugs coadministered into a circuit, significant decreases in extraction and increases in drug recovery (2.5-109%) were found, suggesting dosing adjustments may be needed. This study highlights the need for additional studies of drug coadministration within CRRT circuits to describe complex drug-circuit and drug-drug interactions to provide dosing guidance in pediatric CRRT patients.