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Clearance of Amlodipine, Fentanyl, Fluconazole, Methylprednisolone, and Midazolam by Continuous Renal Replacement
Autumn M McKnite1, Carina E Imburgia2, Danielle J Green2,3
1From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
Insights
Drug loss in continuous renal replacement therapy (CRRT) circuits affects critically ill children. This study quantified drug interactions, revealing variable drug recovery and the need for adjusted dosing in pediatric CRRT patients.
Area of Science:
- Pharmacology
- Nephrology
- Critical Care Medicine
Background:
- Critically ill pediatric patients on continuous renal replacement therapy (CRRT) face high mortality rates (30-70%).
- Altered drug exposure due to drug-CRRT circuit interactions contributes to suboptimal therapeutic outcomes.
- Drug loss occurs via hemofilter clearance and adsorption to circuit components, impacting pharmacokinetics.
Purpose of the Study:
- To quantify drug-circuit interactions for amlodipine, fentanyl, fluconazole, methylprednisolone, and midazolam.
- To assess the impact of individual and combined drug administration on drug loss within CRRT circuits.
- To inform dosing adjustments for pediatric patients undergoing CRRT.
Main Methods:
- Utilized ex vivo, closed-loop, blood-primed CRRT circuits.
- Administered five drugs individually and in combination to mimic therapeutic concentrations.
- Measured drug concentrations in plasma and effluent over time to determine drug recovery and circuit extraction.
Main Results:
- Observed variable drug extraction by the CRRT circuit for individually administered drugs (mean plasma recovery 0.4-49%).
- Found significant decreases in drug extraction and increased drug recovery (2.5-109%) when drugs were coadministered.
- Demonstrated complex drug-circuit and drug-drug interactions impacting drug exposure.
Conclusions:
- Drug-CRRT circuit interactions significantly alter drug pharmacokinetics in critically ill children.
- Drug coadministration exacerbates these interactions, necessitating careful consideration for dosing adjustments.
- Further research is crucial to establish precise dosing guidelines for pediatric CRRT patients to optimize drug therapy and improve outcomes.
Abstract:
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.
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