The Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in a Critically Ill Pediatric Patient Receiving Extracorporeal Membrane Oxygenation and Continuous Venovenous Hemodialysis

Abstract

This report details the pharmacokinetics of oseltamivir and oseltamivir carboxylate following administration of high-dose oseltamivir in a critically ill child receiving extracorporeal membrane oxygenation (ECMO) and continuous venovenous hemodialysis (CVVHD). A 6-year-old critically ill male patient suffering from a presumed viral illness was transferred to our institution's pediatric intensive care unit from an outside hospital after developing respiratory failure and cardiomegaly. ECMO and oseltamivir therapy were initiated upon admission, and CVVHD was started on hospital day 3. Pharmacokinetic sampling occurred at an oseltamivir dose of approximately 4 mg/kg on hospital day 6. The patient's oseltamivir and oseltamivir carboxylate area under the plasma concentration time curves for the 12-hour dosing interval (AUC 0-12 ) were 30.5 and 905 ng/mLhr, respectively. Drug clearance by CVVHD was 31.6 mL/min for oseltamivir and 26.9 mL/min for oseltamivir carboxylate. Pre-and postoxygenator oseltamivir and oseltamivir carboxylate plasma concentrations did not differ substantially. The patient's oseltamivir carboxylate plasma concentrations remained well above the reported mean 50% inhibitory concentration for 2009 pandemic H1N1 virus. However, despite receiving twice the standard dose of oseltamivir, the oseltamivir carboxylate AUC 0-12 in our patient was less than that reported in noncritically ill pediatric subjects. The reduced oseltamivir carboxylate AUC 0-12 found in our patient was most likely due to decreased drug absorption.INDEX TERMS continuous renal replacement therapy, dialysis, extracorporeal membrane oxygenation, influenza, oseltamivir J Pediatr Pharmacol Ther 2012;17(2):173-176

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients

“…This drug was recommended for severe influenza A (H1N1) infection during the 2009 novel influenza H1N1 pandemic . Previous studies of children have indicated that changes in oseltamivir PK during ECMO were not significant . In a prospective case study of 3 children (6‐15 years old), the oseltamivir dosage was doubled and CVVH was performed following the ECMO protocol.…”

“…However, owing to the limited sample size, a dosing recommendation could not be made . An analysis of the other 6‐year‐old child revealed that the differences in oseltamivir and oseltamivir carboxylate concentrations between the pre‐oxygenator and post‐oxygenator of ECMO were small, suggesting little drug removal by the oxygenator during ECMO …”

“…52 Previous studies of children have indicated that changes in oseltamivir PK during ECMO were not significant. 19,53,54 In a prospective case study of 3 children (6-15 years old), the oseltamivir dosage was doubled and CVVH was performed following the ECMO protocol. Two of 3 patients achieved high plasma concentrations for oseltamivir carboxylate with marked variance.…”

“…54 An analysis of the other 6-year-old child revealed that the differences in oseltamivir and oseltamivir carboxylate concentrations between the pre-oxygenator and post-oxygenator of ECMO were small, suggesting little drug removal by the oxygenator during ECMO. 53 In one prospective population study, the PK parameters of oseltamivir carboxylate in 14 adult ECMO patients were compared with values reported in healthy volunteers. This study demonstrated a significant increase in Vss (179 vs 26 L) during ECMO ( Table 2).…”

Influenza virus-related critical illness: prevention, diagnosis, treatment

“…Studies indicate that oseltamivir administered orally or via oro/naso-gastric tube is well absorbed in critically ill patients and reaches plasma levels comparable to those in ambulatory patients [80]. Similarly, several observational studies indicate that enteric oseltamivir reaches comparable plasma concentrations to non-critically ill patients in those receiving extracorporeal membrane oxygenation (ECMO) and renal replacement therapy [80][81][82][83][84][85][86][87], although dosing should be reduced in patients with significant renal impairment. There is scant evidence that increased NAI dosing (e.g., twice daily dosing) in critically ill patients provides additional clinical benefit than standard dosing [80,[88][89][90][91][92].…”