The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies

Abstract

Objective: Acetaminophen-induced fulminant hepatic failure is associated with acute kidney injury, metabolic acidosis, and fluid and electrolyte imbalances, requiring treatment with renal replacement therapies. Although antidote, acetylcysteine, is potentially extracted by renal replacement therapies, pharmacokinetic data are lacking to guide potential dosing alterations. We aimed to determine the extracorporeal removal of acetylcysteine by various renal replacement therapies. Methods: Simultaneous urine, plasma and effluent specimens were serially collected to measure acetylcysteine concentrations in up to three stages: before, during and upon termination of renal replacement therapy. Alterations in pharmacokinetics were determined by applying standard pharmacokinetic equations. Results: Over 2 years, 10 critically ill patients in fulminant hepatic failure requiring renal replacement therapy coincident with acetylcysteine were consecutively enrolled. All 10 patients required continuous venovenous hemofiltration (n = 10) and 2 of the 10 also required hemodialysis (n = 2). There was a significant alteration in the pharmacokinetics of acetylcysteine during hemodialysis; the area under the curve (AUC) decreased 41%, the mean extraction ratio was 51%, the mean hemodialytic clearance was 114.01 ml/kg/h, and a mean 166.75 mg/h was recovered in the effluent or 41% of the hourly dose. Alteration in the pharmacokinetics of acetylcysteine during continuous venovenous hemofiltration did not appear to be significant: the AUC decreased 13%, the mean clearance was 31.77 ml/kg/h and a mean 62.12 mg/h was recovered in the effluent or 14% of the hourly dose. Conclusions: There was no significant extraction of acetylcysteine from continuous venovenous hemofiltration. In contrast, there was significant extracorporeal removal of acetylcysteine during hemodialysis. A reasonable dose adjustment may be to double the IV infusion rate or possibly supplement with oral acetylcysteine during hemodialysis.

Keywords:

• N-acetylcysteine
• Hemodialysis
• Continuous venovenous hemofiltration
• Renal replacement therapy
• Pharmacokinetics
• Fulminant hepatic failure

Acknowledgements

Substantial input in the study design was provided Dr Judy Benstein, Assistant Professor, Director of the Nephrology Fellowship Program at New York University Langone Medical Center. Dr Michael H. Schwenk, Pharm. D. Clinical Pharmacist at Columbia University, New York, made a significant contribution with his expertise and guidance in renal replacement therapy pharmacokinetics. Financial support for this study was provided by the American College for Medical Toxicology (ACMT) and McNeil Products Grant for Acetaminophen Related Research.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.