Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

Abstract

Background: Whether the enteric absorption of the neuraminidase inhibitor oseltamivir is impaired in critically ill patients is unknown. We documented the pharmacokinetic profile of oseltamivir in patients admitted to intensive care units (ICUs) with suspected or confirmed pandemic (H1N1) influenza.

Methods: We included 41 patients 18 years of age and older with suspected or confirmed pandemic (H1N1) influenza who were admitted for ventilatory support to nine ICUs in three cities in Canada and Spain. Using tandem mass spectrometry, we assessed plasma levels of oseltamivir free base and its active metabolite carboxylate at baseline (before gastric administration of the drug) and at 2, 4, 6, 9 and 12 hours after the fourth or later dose.

Results: Among the 36 patients who did not require dialysis, the median concentration of oseltamivir free base was 10.4 (interquartile range [IQR] 4.8-14.9) microg/L; the median concentration of the carboxylate metabolite was 404 (IQR 257-900) microg/L. The volume of distribution of the carboxylate metabolite did not increase with increasing body weight (R2=0.00, p=0.87). The rate of elimination of oseltamivir carboxylate was modestly correlated with estimations of creatinine clearance (R2=0.27, p<0.001). Drug clearance in the five patients who required continuous renal replacement therapy was about one-sixth that in the 36 patients with relatively normal renal function.

Interpretation: Oseltamivir was well absorbed enterically in critically ill patients admitted to the ICU with suspected or confirmed pandemic (H1N1) influenza. The dosage of 75 mg twice daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. Adjustment of the dosage in patients with renal dysfunction requiring continuous renal replacement therapy is appropriate; adjustment for obesity does not appear to be necessary.

Figure 1

Average plasma concentrations of oseltamivir carboxylate over one dosing interval in 34 patients admitted to intensive care unit (ICU) with suspected or confirmed pandemic (H1N1) influenza who did not require dialysis (primary study cohort). Oseltamivir doses were normalized to 75 mg twice daily. The horizontal line in the middle of each box indicates the median, and the top and bottom borders of the box mark the 25th and 75th percentiles, respectively. The whiskers are 1.5 times the upper and lower interquartile ranges. The outlier (black dot) indicates a case with values between 1.5 and 3 box lengths from one side of the range. The extreme values (*) indicate cases with values more than 3 box lengths from the 75th or 25th percentile.

Figure 2

Average plasma concentrations of oseltamivir carboxylate over one dosing interval in five patients admitted to ICU with suspected or confirmed pandemic (H1N1) influenza who received continuous renal replacement therapy. Oseltamivir doses were normalized to 75 mg twice daily. The horizontal line in the middle of each box indicates the median, and the top and bottom borders of the box mark the 25th and 75th percentiles, respectively. The whiskers are 1.5 times the upper and lower interquar-tile ranges. The outlier (black dot) indicates a case with values between 1.5 and 3 box lengths from one side of the range.

Figure 3

Scatterplot showing the relation between body weight and volume of distribution for oseltamivir carboxylate. Solid line represents the linear regression fit across all patients. F = systemic bioavailability.

Figure 4

Scatterplot showing the relation between normalized creatinine clearance and the elimination rate of oseltamivir carboxylate. Solid line represents the linear regression fit across all patients.