Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis and/or Extracorporeal Membrane Oxygenation

Abstract

To investigate oseltamivir and oseltamivir carboxylate pharmacokinetics in critically ill patients who were receiving continuous venovenous hemodialysis (CVVHD) and/or extracorporeal membrane oxygenation (ECMO). Prospective, open-label, pharmacokinetic study. Intensive care units of an academic medical center. Thirteen critically ill patients aged 13years or older with suspected or confirmed H1N1 influenza who had a prescription for oseltamivir and were concurrently receiving CVVHD and/or ECMO between October 2009 and January 2010. Oseltamivir 150mg was administered nasogastrically or nasoenterically every 12hours. Blood samples were collected at baseline and at 1, 2, 4, 6, 8, 10, and 12hours after administration of the fourth oseltamivir dose or subsequent doses. In patients receiving CVVHD, effluent also was collected at the same time points. Urine was collected throughout the 12-hour dosing interval. Eight patients received CVVHD only, four patients received both CVVHD and ECMO, and one patient received ECMO only. Pharmacokinetic parameters for the patient who received only ECMO were not reported. The median maximum plasma concentration and area under the plasma concentration-time curve for the 12-hour dosing interval (AUC(0-12) ) for the remaining 12 patients were 83.4ng/ml and 216ng•hour/ml, respectively, for oseltamivir and 2000ng/ml and 21,500ng•hour/ml, respectively, for oseltamivir carboxylate. Mean clearance due to CVVHD was 33.8ml/minute for oseltamivir and 50.2ml/minute for oseltamivir carboxylate. For patients who received ECMO, no substantial differences between pre- and post-ECMO oxygenator plasma concentrations were found for oseltamivir or oseltamivir carboxylate. Although the optimal pharmacokinetic-pharmacodynamic targets for oseltamivir carboxylate remain unclear, in the patients receiving CVVHD with or without ECMO, a regimen of oseltamivir 150mg every 12hours yielded a median oseltamivir carboxylate AUC(0-12) considerably higher than would be expected in non-critically ill patients receiving the same dosage regimen.