An in vitro study of elimination of oseltamivir carboxylate by haemofiltration

Introduction

Oseltamivir is the drug of choice for treatment of avian influenza A/H5N1 infection. One-quarter of patients with influenza A/H5N1 develop acute renal failure. A proportion will require haemofiltration. There are no data to determine the elimination of oseltamivir carboxylate (the active metabolite) by haemofiltration. An in vitro study to determine elimination by measuring the adsorption and sieving coefficient of oseltamivir carboxylate using two haemofilter types was undertaken.

Methods

An in vitro one-compartment model of continuous veno-venous haemofiltration was used. In phase 1 oseltamivir carboxylate adsorption to the haemofilter and circuit was studied by circulating a blood–crystalloid mixture containing clinically relevant concentrations of oseltamivir carboxylate through a haemofilter circuit and returning the ultrafiltrate to the mixing chamber. In phase 2 the ultrafiltrate was removed and replaced with a bicarbonate-based fluid to enable calculation of the sieving coefficient. The study was repeated 10 times with two haemofilter types: polyamide and polyacrylonitrile (PAN). Finally, oseltamivir carboxylate was added to the blood–crystalloid mixture without circulation through the circuit to determine its stability in solution. Blood samples collected were assayed by HPLC-MS/MS.

Results

Oseltamivir carboxylate remained stable in solution (mean percentage change from baseline at 30 min: +3.97%, at 60 min: +1.91%, at 90 min: +2.36%). The mean ± SD initial oseltamivir carboxylate concentrations for the PAN (346 ± 85 μg/l) and polyamide (453 ± 185 μg/l) showed no significant difference. The mean ± SD adsorption at 90 min was 58.18 ± 17.84 μg for PAN and 75.22 ± 36.88 μg for polyamide haemofilters. There was no statistical difference in adsorption between the haemofilters. The initial drug concentration was a significant predictor of adsorption (r² = 0.734). The mean ± SD sieving coefficient of oseltamivir carboxylate for PAN (1.06 ± 0.04) and polyamide (1.03 ± 0.06) haemofilters showed no statistical difference between the haemofilters.

Conclusion

Total adsorption is low and unlikely to be of clinical significance. Adsorption and the sieving coefficient are independent of the type of haemofilter membrane. The sieving coefficient of oseltamivir carboxylate is 1, therefore clearance during haemofiltration can be estimated from the ultrafiltration rate.