Oseltamivir Is Adequately Absorbed Following Nasogastric Administration to Adult Patients with Severe H5N1 Influenza

Abstract

In the absence of a parenteral drug, oral oseltamivir is currently recommended by the WHO for treating H5N1 influenza. Whether oseltamivir absorption is adequate in severe influenza is unknown. We measured the steady state, plasma concentrations of nasogastrically administered oseltamivir 150 mg bid and its active metabolite, oseltamivir carboxylate (OC), in three, mechanically ventilated patients with severe H5N1 (male, 30 yrs; pregnant female, 22 yrs) and severe H3N2 (female, 76 yrs). Treatments were started 6, 7 and 8 days after illness onset, respectively. Both females were sampled while on continuous venovenous haemofiltration. Admission and follow up specimens (trachea, nose, throat, rectum, blood) were tested for RNA viral load by reverse transcriptase PCR. In vitro virus susceptibility to OC was measured by a neuraminidase inhibition assay. Admission creatinine clearances were 66 (male, H5N1), 82 (female, H5N1) and 6 (H3N2) ml/min. Corresponding AUC0–12 values (5932, 10,951 and 34,670 ng.h/ml) and trough OC concentrations (376, 575 and 2730 ng/ml) were higher than previously reported in healthy volunteers; the latter exceeded 545 to 3956 fold the H5N1 IC50 (0.69 ng/ml) isolated from the H5N1 infected female. Two patients with follow-up respiratory specimens cleared their viruses after 5 (H5N1 male) and 5 (H3N2 female) days of oseltamivir. Both female patients died of respiratory failure; the male survived. 150 mg bid of oseltamivir was well absorbed and converted extensively to OC. Virus was cleared in two patients but two patients died, suggesting viral efficacy but poor clinical efficacy.

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

“…[9][10][11][12][13][14][15] Although there was some delay in the gastrointestinal absorption of the drug after nasogastric or nasojejunal administration (Table 2), the final area under the curve for the carboxylate metabolite at the 75-mg dose in our primary study cohort was also similar to values found in ambulatory patients. 12,13,15 The achieved concentration of oseltamivir in relation to the sensitivity of the influenza virus is associated with the probability of viral eradication and clinical cure in vivo.…”

“…10 We found that clearance of the metabolite during dialysis was about one-fifth to one-sixth that of patients with relatively normal renal function. With regards to exposure to the carboxylate metabolite from the 75-mg, twice-daily regimen, the area under the curve (normalized to the 75-mg, twice-daily dose) was almost six times higher in patients receiving dialysis than in those with relatively normal renal function (Table 2).…”

Pandemic influenza A (H1N1) 2009: the experience of the first six months

“…High dose oseltamivir (150 mg twice daily) and prolonged prophylaxis at normal treatment doses have been shown to be safe and well tolerated (62), and high dose treatment administered via nasogastric tube was shown to have a good pharmocokinetic profile in severe influenza A (H5N1) infection (63). No published data have shown high dose treatment to be more effective than treatment with normal doses (58).…”

Antiviral Drugs Zanamivir and Oseltamivir Found in Wastewater and Surface Water in Osaka, Japan

“…Widespread detection of antiviral drugs in wastewaters and surface waters particularly during seasonal and pandemic influenza cases (Bartels and Tumpling, 2008;Soderstrom et al, 2009;Prasse et al, 2010;Ghosh et al, 2010a and b;Takanami et al, 2010a), and their potential negative consequences to aquatic ecology and humans (Taylor et al, 2008;Straub, 2009) has recently attracted considerable attention from scientific communities. After administration, the drugs and their metabolites are excreted, carried away in sewers, passed through treatment facilities (Fick et al, 2007;Accinelli et al, 2007Accinelli et al, , 2010aAccinelli et al, , and 2010bSlater et al, 2011) and reached water bodies.…”