Oseltamivir dosing with haemofiltration

Introduction

In the current pandemic it is likely that some patients will be admitted to hospital and require respiratory support including mechanical ventilation. These patients are likely to have a profound systemic inflammatory response syndrome (SIRS); consequently they may have multiorgan failure (MOF) requiring renal replacement therapy (RRT) with haemofiltration. Two questions then arise - what dose of oseltamivir (Tamiflu) should we give these patients to shorten the duration of the H1N1 infection? How should we modify the dose in response to altered renal drug clearance and in those requiring RRT?

Methods

A young adult female patient with H1N1 infection and MOF was given oseltamivir 75 mg BD nasogastrically. Failure to respond changed the risk: benefit ratio and justified doubling the dose despite uncertainties over an overall reduced clearance. Enteral nutrition absorption was uncertain, and thus we sampled her blood to ensure adequate oseltamivir absorption and that activation of the pro-drug was not inhibited. We undertook serial sampling for blood concentration assay to determine the pharmacokinetic parameters in this difficult scenario. Blood samples were collected in plain serum tubes (without sodium fluoride). The samples were spun and refrigerated within half an hour, then batched and shipped to Bangkok for drug concentration measurement.

Results

We report both the parent oseltamivir phosphate (OP) and that of the active metabolite oseltamivir carboxylate (OC). OP levels were low at 10 to 77 ng/ml. but OC concentrations were high at 2,600 to 5,000 ng/ml.

Conclusions

The population normal parameter for half-life OP is 1 hour and for OC it is 3 to 5 hours. A single dose of 150 mg OP is expected to achieve an OP level of 50 to 150 ng/ml and an OC level of 1,000 to 1,500 ng/ml. Our slightly low OP levels are likely to be due to ex vivo hydrolysis in the collection tube due to a lack of esterase inhibitor. The high OC levels are most probably due to reduced renal elimination despite being on haemofiltration. Our concerns were focused on the possibility of viral mutation (subsequently shown to be negative) or poor enteral absorption/activation. What we found was that 150 mg BD produces more than adequate OC levels to treat H1N1 infection.