gs-4071 and Critical-Illness

Extracorporeal membrane oxygenation (ECMO) is known to affect pharmacokinetics and hence optimum dosing. The aim of this open label, prospective study was to investigate the pharmacokinetics of oseltamivir (prodrug) and oseltamivir carboxylate (active metabolite) during ECMO. Fourteen adult patients with suspected or confirmed H1N1 influenza were enrolled in the study. Oseltamivir 75 mg was enterally administered twice daily and blood samples for pharmacokinetic assessment were taken on day 1 and 5. A multi-compartmental model to describe the pharmacokinetics of oseltamivir and oseltamivir carboxylate was developed using a non-linear mixed effects modelling approach. The median (range) clearance of oseltamivir carboxylate was 15.8 (4.8-36.6) l/hour, lower than the reported mean value of 21.5 l/hour in healthy adults. The median (range) steady state volume of distribution of oseltamivir carboxylate was 179 (61-436) litres, much greater than healthy adults but similar to previous reports in critically ill patients. Substantial 'between subject' variability in systemic exposure to oseltamivir carboxylate was revealed; median (range) area under the curve and Cmax were 4346 (644-13660) ng/hour/ml and 509 (54-1277) ng/ml, respectively. Both area under the curve and Cmax were significantly correlated with serum creatinine (r2=0.37, P=0.02 and r2=0.29, P=0.02, respectively). Systemic exposure to oseltamivir carboxylate following the administration of enteral oseltamivir 75 mg twice daily in adult ECMO patients is comparable to those in ambulatory patients and far in excess of concentrations required to maximally inhibit neuraminidase activity of the H1N1 virus. Dosage adjustment for ECMO, per se, appears not to be necessary; however, doses should be reduced in patients with renal dysfunction.

Topics: Adult; Antiviral Agents; Area Under Curve; Creatinine; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Nonlinear Dynamics; Oseltamivir; Tissue Distribution

Topics: Adult; Aged; Antiviral Agents; Area Under Curve; Critical Illness; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Oseltamivir; Pandemics

The neuraminidase inhibitor oseltamivir is a recommended treatment for influenza A (H1N1) infection. In rare cases, some patients develop influenza-associated multiple organ failures, requiring rescue therapies such as extracorporeal membrane oxygenation (ECMO) or continuous venovenous hemodiafiltration (CVVHDF). This study was designed to evaluate the impact of ECMO and CVVHDF on the pharmacokinetics of oseltamivir carboxylate (OC) in critically ill patients with pandemic (H1N1) influenza treated with oseltamivir.. Seven critically ill patients on venovenous ECMO for severe pandemic (H1N1) influenza associated with acute respiratory distress syndrome were treated with various doses of oseltamivir (75 or 150 mg twice daily). Because of acute kidney injury, 3 of them also received CVVHDF. OC, the active form of oseltamivir, was quantified in plasma, and main pharmacokinetic parameters were determined.. OC Cmax (1029 ± 478 ng/mL) and area under the curve (9.00 ± 4.52 mcg·h/mL) for patients on ECMO with preserved renal function were comparable with those of healthy volunteers or noncritically ill patients. Patients both on ECMO and CVVHDF had 4-to 5-fold higher OC Cmax and area under the curve.. ECMO by itself did not impact on the pharmacokinetics of OC. However, the drug accumulated in the plasma of patients on ECMO who also received CVVHDF for renal failure. Based on these results, we recommend that oseltamivir dosage should be decreased and plasma levels of OC be monitored in patients receiving CVVHDF because of acute kidney injury.

Topics: Acute Kidney Injury; Adult; Antiviral Agents; Area Under Curve; Critical Illness; Dose-Response Relationship, Drug; Extracorporeal Membrane Oxygenation; Female; Hemodiafiltration; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Oseltamivir; Pandemics; Respiratory Distress Syndrome; Young Adult

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 13 years 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 150 mg was administered nasogastrically or nasoenterically every 12 hours. Blood samples were collected at baseline and at 1, 2, 4, 6, 8, 10, and 12 hours 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 83.4 ng/ml and 216 ng•hour/ml, respectively, for oseltamivir and 2000 ng/ml and 21,500 ng•hour/ml, respectively, for oseltamivir carboxylate. Mean clearance due to CVVHD was 33.8 ml/minute for oseltamivir and 50.2 ml/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 150 mg every 12 hours yielded a median oseltamivir carboxylate AUC(0-12) considerably higher than would be expected in non-critically ill patients receiving the same dosage regimen.

Topics: Academic Medical Centers; Adolescent; Adult; Antiviral Agents; Area Under Curve; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Oseltamivir; Prospective Studies; Renal Dialysis; Time Factors

During the 2009 H1N1 influenza pandemics, the concentrations of oseltamivir (O) and its active metabolite (oseltamivir carboxylate [OC]) were determined in 11 children (1 month to 16 years of age) admitted to intensive care units for presumed severe H1N1 infection. They received oseltamivir phosphate (OP) nasogastrically at doses between 1.5 and 6.8 mg/kg of body weight. High OC concentrations were found, with a mean level of 678 ± 535 μg/liter. The mean OP concentration was 27 ± 52 μg/liter. No marked side effect was reported.

Topics: Adolescent; Antiviral Agents; Child; Child, Preschool; Critical Illness; Female; Humans; Infant; Influenza, Human; Intensive Care Units; Intubation, Gastrointestinal; Male; Oseltamivir; Reverse Transcriptase Polymerase Chain Reaction

To evaluate the effect of extracorporeal membrane oxygenation (ECMO) support on pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in children.. Steady state 0-12 hour pharmacokinetic sampling was performed in new influenza A (H1N1) infected children treated with oseltamivir while on ECMO support. Cmax, Cmin and AUC(0-12 h) were calculated. The age-specific oseltamivir dosage was doubled to counter expected decreased plasma drug concentrations due to increased volume of distribution on ECMO support.. Three patients were enrolled aged 15, 6 and 14 years in this pharmacokinetic case series. For two children the OC plasma concentrations were higher than those found in children and adults not on ECMO. These increased plasma concentrations related to the increased oseltamivir dosage and decreased kidney function. In one patient suboptimal plasma concentrations coincided with a decreased gastric motility.. Oseltamivir pharmacokinetics do not appear to be significantly influenced by ECMO support. Caution is required in case of nasogastric administration and decreased gastric motility. Due to the limited number of (paediatric) patients available further multicenter studies are warranted.

Topics: Adolescent; Antiviral Agents; Area Under Curve; Child; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Humans; Male; Oseltamivir; Prospective Studies