Oseltamivir Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation Support

Abstract

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 nonlinear 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 C max were 4346 (644-13660) ng/hour/ml and 509 (54-1277) ng/ml, respectively. Both area under the curve and C max were significantly correlated with serum creatinine (r 2 =0.37, P=0.02 and r 2 =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.

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

“…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 ) . This might reflect the expanded circulating volume .…”

“…However, critical illnesses, such as oedema, capillary leak syndrome, third spacing and large volumes of blood products administered to patients during ECMO, could also cause expansion of the Vd . The mean CL of oseltamivir carboxylate was significantly decreased in ECMO patients because oseltamivir carboxylate is primarily eliminated renally, and ECMO patients have substantially decreased renal function compared to that of healthy volunteers . Furthermore, they often require CVVHDF, which results in drug accumulation .…”

“…This suggested that drug binding to oxygenators was not a relevant cause of the decreased CL . The decreased CL may cause average oseltamivir carboxylate concentrations to exceed the concentrations needed to maximally inhibit the neuraminidase activity of the H1N1 virus . However, oseltamivir is well tolerated and its main adverse effect is gastrointestinal distress .…”

“…Therefore, dose adjustment for ECMO may not be necessary, and doses should be reduced in renally impaired patients. Owing to variability in oral bioavailability, PK variability should be considered according to the route of administration …”

Pharmacokinetics and Dosing of Anti-infective Drugs in Patients on Extracorporeal Membrane Oxygenation: A Review of the Current Literature

“…79–81 Fourteen patients received standard oseltamivir dosing of 75 mg twice daily. 58,81 Mean systemic exposures at this dose were well above the MIC for H1N1 and comparable to those seen in non-ECMO patients and healthy volunteers. However, there was significant variability of PK parameters between patients in this study, which the authors attributed to differences in enteral absorption and renal function.…”