"Critically ill patients exhibit defects in gastrointestinal absorption because of impaired gut perfusion, edema of the bowel wall and ileus as a consequence of critical illness and shock," write Anand Kumar, MD, from the Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada, and colleagues. "Whether the enteric [intestinal] absorption of oseltamivir is impaired in such patients is unknown."
Researchers studied 41 patients (mean age, 41 years) who were admitted to 9 intensive care units in 3 cities in Canada and Spain, each of whom had respiratory failure believed to be caused by H1N1. All participants were using a ventilator, and 8 patients also had significant kidney disease. Of those 8 patients, 7 required dialysis, and 5 of the 7 needed continuous renal replacement therapy.
During the study period, most of the critically ill patients received the standard dose of oseltamivir, 75 mg 2 times a day — the same regimen as that of healthier subjects. In only a few instances did physicians administer the WHO-recommended double dose of 150 mg twice a day. Medications were taken orally or through nasogastric intubation.
Using tandem mass spectrometry, researchers evaluated plasma levels of oseltamivir free base and its active metabolite carboxylate. These assessments took place before the drug was given and at 2, 4, 6, 9, and 12 hours after a minimum of 4 doses.
Drug Concentration More Than Adequate
For the 36 patients not undergoing dialysis, the study resulted in the following findings:
Oseltamivir free base median plasma concentration was 10.4 μg/L, which is more than 2000- to 4000-fold higher than is necessary to restrain the virus.
The median concentration of the carboxylate metabolite was 404 μg/L.
Carboxylate metabolite's volume of distribution did not rise with increasing body weight (R2, 0.00; P = .87).
The elimination rate of oseltamivir carboxylate had a slight association with creatinine clearance estimations (R2, 0.27; P < .001).
In the 5 patients requiring continuous renal replacement therapy, drug clearance was about one sixth of that found in the other subjects.
"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," the authors write. "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."
Limitations to the study included an inability to determine whether lung injury connected to severe pneumonia decreased oseltamivir penetration into pulmonary tissue, which could result in lower drug concentrations in the lungs. Researchers also noted that they did not evaluate the effect of antiviral density on the pulmonary viral load.
The study results are not conclusive, according to Donald Kennedy, MD, professor of infectious diseases, Saint Louis University School of Medicine, Missouri. In an interview with Medscape Infectious Diseases, he pointed out that researchers did not address whether increasing the dose to 150 mg might change outcomes.
"They didn't study the double dose in sick people; they studied the regular dose in sick people," Dr. Kennedy said. "What they showed is the regular dose in sick people appears to give the same levels as the regular dose to people in the original Tamiflu studies, which were relatively healthy people." Dr. Kennedy was not involved in the study.
r. Kumar told Medscape Infectious Diseases that he is currently presiding over a larger study to test the 150-mg dose.
"There are still other reasons why higher doses may be helpful," Dr. Kumar said. "We hope we'll have a definite answer to this in a year or two."
WHO Will Consider Changes to Dosing Recommendations
Nikki Shindo, MD, medical officer, Epidemic and Pandemic Alert and Response Department, WHO, Geneva, Switzerland, called the study "thorough and sound." Although she would prefer to see the results replicated first, Dr. Shindo said WHO will take the findings into account for new guidelines to be released in July.
"I think we can count it as very important evidence that will impact our recommendations. If the results are proven elsewhere in the world, that will increase its strength," Dr. Shindo said in an interview with Medscape Infectious Diseases.
Dr. Kumar said that he is aware of several studies attempting to replicate his results. He is optimistic that further research will confirm his findings.
"It's a very simple study. You give the patient the drug, you measure it in their blood, and assuming that the assay is accurate and this was done by a commercial laboratory, you would get similar results," Dr. Kumar said. "There is not a lot of wiggle room or expectations that you would see anything substantially different."
The Public Health Agency of Canada and Hoffmann-La Roche, manufacturer of Tamiflu, supported this study. Dr. Anand Kumar is leading another study of H1N1 and oseltamivir therapy that is also supported by Hoffmann-La Roche, and coauthor Dr. Stéphane Ahern is president of the Comité scientifique de l'inscription, Conseil du médicament du Québec, an advisory committee. The study authors have disclosed no other relevant financial relationships.