Severely Ill Patients With H1N1 Do Not Require Higher Tamiflu Doses

Patients who are gravely ill with pandemic H1N1 influenza do not need a higher dose of oseltamivir (Tamiflu, Roche Laboratories), according to a study published online February 16 in the Canadian Medical Association Journal. The finding contradicts World Health Organization (WHO) dosing recommendations.
"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.

Putting Tamiflu To The Test

The efficiency of influenza virus drugs, such as Tamiflu, can now be tested thanks to equipment at the University of Canterbury.
The research will be carried out in the University's world-class Biomolecular Interaction Centre (BIC) laboratory in collaboration with Environmental Science & Research (ESR) and the National Centre for Biosecurity and Infectious Disease.
This research project is possible thanks to specialist state-of-the-art equipment and new BioRad certification as a reference lab.
"Central to our equipment is the surface plasmon resonance (SPR) that we got from BioRad," said BIC Co-director Professor Conan Fee (Chemical and Process Engineering).
UC was the first in the southern hemisphere to buy a BioRad SPR ProteOn XPR 36 which is used to determine the specificity, affinity and kinetics of the interactions of biomolecules. The SPR also enables researchers to focus on testing scientific hypothesis rather than driving the instrument.
Professor Fee said that it had some "nice features, essentially it allows us to do a lot of research, get many results and very quickly".
Using the SPR, anti-viral drugs such as Tamiflu will be tested for efficiency in combating strains of influenza.
"Where the influenza virus mutates and becomes resistant to medication, we are developing new methods by which we can explore those mechanisms - this is a project that has come to us directly because of SPR," Professor Fee said.
"We aim to test this in our instrument to see if anti-viral drugs work or the viruses have developed resistance."
Another collaboration includes research with the Wakefield Gastroenterology Centre in Wellington.
The Wakefield Gastroenterology Centre approached BIC directly as a result of having the SPR and since has developed a collaboration looking at type 2 diabetes. The research is looking at the relationship between gastric bypass surgery and the disappearance of insulin resistance in diabetic patients.
"Professor Richard Stubbs [gastric by-pass surgeon and Adjunct Professor at Otago University's Wellington Clinical School of Medicine] came to visit UC to offer a library of blood and serum samples from gastric bypass patients," said Professor Fee.
"They are going to provide the samples and we will look at the reactions between insulin and its receptor using the SPR looking for factors and the mechanism of why diabetics' symptoms switch off after gastric bypass surgery."
BIC also has collaborations with Plant and Food, Lincoln University, the University of Otago Christchurch School of Medicine, AgResearch and more recently Industrial Research Ltd and Fonterra.
"BIC is working well with new collaborations, even in its early stage, and we are all very enthusiastic," said Professor Fee.

When swine flu pandemic hits home

By Steve Sternberg, USA TODAY
Joan Bishop's thoughts trend toward disaster. Earthquakes, hurricanes, "dirty bombs," weapons of mass destruction, killer pandemics — she has studied them all.
But Bishop, 46, of Fairfax, Va., says her expertise did little to stop the H1N1 pandemic from landing on her doorstep. Despite taking all the recommended precautions, two of her three daughters, Beri, 10, and Bailey, 13, contracted swine flu. Each posed a different challenge because their unique risks — Beri's autism and epilepsy and Bailey's asthma — made them more difficult to treat.
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What's more, Bishop says, her expertise intensified her concerns about her children.
"I know too much," she says.
The worst-case scenarios 
A disaster preparedness expert for the consulting firm Booz Allen Hamilton, Bishop has helped draft pandemic plans for the Department of Defense and the Department of Health and Human Services. She has absorbed the medical literature and studied the case histories.
As her children grew sicker, she was overwhelmed with anxiety over what might happen next. She couldn't shake the worst-case scenarios that were running through her mind.
"I knew what was happening medically. I've read the autopsy reports. Seeing those was scary," she says.
The Bishop family's ordeal illustrates one of the central paradoxes of the pandemic. Unlike seasonal flu, H1N1 has taken a disproportionate toll on children.
Beri's symptoms set in on Nov. 1, when H1N1 vaccine was still in short supply. Right after Halloween, Beri developed a high fever and respiratory symptoms.
Her pediatrician diagnosed Beri with flu complicated by pneumonia. She prescribed antibiotics and the antiviral drug Tamiflu. But Beri, who already was taking medication for seizures and an inactive thyroid, was gripped with anxiety about taking any more pills.
"She was paralyzed with fear of choking, because she was coughing so much," Bishop says.
Her parents' urging to follow the doctors' orders hardened her resistence. Soon she refused to take any medication at all. "I was stressed that she was not taking her antiviral and antibiotics," Bishop says. It was Beri's refusal to take her anti-seizure medication "that almost did me in," her mother says. "You can't have a seizure on top of this," she implored her daughter.
Her parents tried liquid Tamiflu, Bishop says, but that didn't help: "It tasted like gasoline." The usual advice — "put it in applesauce" — didn't work. Ultimately, she ended up washing the drug down with big gulps of cola. She still refused to take her antibiotics, so doctors began giving them to her intravenously and through injections. Eventually, the medicine helped, and Beri began getting better.
Then, in the first week of December, back from a family vacation in California, Bailey got the flu, complicated by an ear infection.
She was diagnosed on Sunday, Dec. 6. Doctors prescribed Tamiflu and antibiotics. By Wednesday, Bishop says, her father took Bailey back to the doctor. "She was having severe symptoms for someone who had been on Tamiflu for four days." A chest X-ray was negative.
Bailey's ordeal worsens 
By Friday, Dec. 11., Bailey's temperature hit 103 degrees and stayed there. She began coughing so persistently that she couldn't sleep. In the early hours of Dec. 12, her parents took her to an urgent-care center because she couldn't breathe. A doctor prescribed oral steroids, drugs known to ease airway congestion.
Based on a new chest X-ray, Bishop says, the doctor diagnosed pneumonia. But three subsequent X-rays and a CT scan of Bailey's chest proved inconclusive. One clue to Bailey's misery may lie in the autopsy research Bishop cites.
The studies, by Jeffrey Jentzen at the University of Michigan and James Gill of New York University and Jeffrey Taubenberger of the National Institute of Allergy and Infectious Diseases, show that unlike most flu viruses, H1N1 can settle deep into the lungs. "We're not sure why," Jentzen said in a recent interview.
A new crisis began on the morning of Christmas Eve, after a visit with Santa Claus at a local mall. Bailey began wheezing, and despite treatments with nebulizers at home, her blood oxygen level began dropping. A doctor recommended that Bailey be admitted to Inova Fairfax hospital, where she stayed for two days.
Since then, she has been sustained on steroids, given orally and through inhalers. "She's better than she was, but she's not back to her full capacity," Bishop says. "Her asthma is worse than before."
Doctors allowed Bailey to stop taking the oral steroids in January. She is slowly getting better, Bishop says, but it may be months before she fully recovers.

Increased Tamiflu dosage not necessary for critically ill H1N1patients

Washington, DC: A new study has found that a high dosage of Tamiflu (oseltamivir) for patients with critical illness is unlikely to be required for the treatment of pandemic (H1N1) influenza. The study has appeared in Canadian Medical Association Journal (CMAJ).
The study goes against the World Health Organization (WHO) guidelines, which say all critically ill patients should be treated with Tamiflu and if the patient was unresponsive to standard doses, or critically ill, a higher dose should be considered. As critically ill patients may have gastrointestinal absorption issues, guidelines suggest higher doses of Tamiflu.
The CMAJ study looked at the gastrointestinal absorption of Tamiflu in 44 patients, 18 years of age or older, with suspected or confirmed pandemic (H1N1) influenza who were admitted to nine ICUs in the two Canadian cities of Winnipeg and Ottawa and Tarragona, Spain, because of respiratory failure. 
"Studying the absorption ability of Tamiflu in the critically ill became a priority with the large number of patients needing ICU and ventilation support," 
Lead author Dr Anand Kumar, Health Sciences Centre, University of Manitoba and coauthors, write: "Also, the number of obese patients suffering from H1N1 related critical illnesses were large which raised the question about whether the dose should be adjusted upwards with increased body weight."
Blood sampling suggested that the 75 mg twice daily dosage of Tamiflu was well absorbed in critically ill patients with respiratory failure. Blood levels of the antiviral were similar or higher than levels in ambulatory patients with a similar dosage. Patients with kidney dysfunction requiring dialysis needed an adjusted dose but adjustment for obesity was not required.
The authors conclude: "The findings of this study suggest that an increased Tamiflu dosage is unlikely to be necessary in such cases based on either insufficient drug absorption or altered distribution pharmacokinetics."

Genentech deal, Tamiflu sales lift Roche

ROCHE Holding reported an 11% increase in second-half profit yesterday, helped by cost savings from its takeover of Genentech and higher demand for swine flu drug Tamiflu.
Profit excluding some costs advanced to Sf4,59bn (4,35bn) from Sf4,15bn a year earlier. Fourth-quarter revenue rose 2,8% to Sf12,65bn, Roche said. That fell short of expectations, according to Birgit Kulhoff, an analyst at Rahn & Bodmer in Zurich.
While Roche benefited from greater than expected Tamiflu demand, which soared as the H1N1 virus spread, sales of the company’s cancer medicines, Rituxan and Herceptin, declined in the fourth quarter, falling short of analysts’ forecasts. It said that performance was affected by wholesalers reducing inventory and was not “a prediction into 2010”.
Numbers from January showed a “healthy trend”, chief financial officer Erich Hunziker said yesterday. 
Roche, based in Basel, Switzerland, maintained its forecast that earnings per share excluding some items would probably rise at a double-digit pace this year at constant exchange rates. 
Revenue was expected to grow in the mid-single-digit range in local currencies this year. The outlook excludes sales of Tamiflu. Roche said it would maintain its dividend policy.
The shares fell Sf2,4, or 1,3%, to Sf178,2 before midday yesterday in Zurich trading. Roche has risen 9,7% in the past year, compared with a 12% gain in the Bloomberg European pharmaceuticals index. 
Roche CEO Severin Schwan dismissed speculation that Novartis could sell its stake in its rival to help pay for acquiring eyecare group Alcon, telling CNBC the talk was “pure speculation”.
The Swiss drug maker repeated that it was targeting savings of Sf1bn a year by next year from the 46,8bn purchase of Genentech.
Roche expects to repay 25% of the debt raised to finance it by the end of this year and to “return to a net cash position” by 2015. 
Revenue from Tamiflu has risen since the outbreak of swine flu in April. The medicine generated Sf3,2bn in sales last year, more than the company’s October estimate of about Sf2,7bn. Tamiflu was likely to generate about Sf1,2bn in sales this year, Roche said yesterday, up from an earlier estimate of Sf700m. 
Sales of the medicine, which has been shown to ease the symptoms of infection with the virus, generated Sf1,2bn in revenue in the fourth quarter, compared with Sf181m a year ago.
The H1N1 virus had been confirmed in more than 209 countries worldwide and had caused at least 14711 deaths as of January 29, the World Health Organisation (WHO) said last week. Swine flu causes little more than a fever and cough in most cases. WHO director-general Margaret Chan said recently that the worst may be over in the northern hemisphere. Bloomberg

Tamiflu sales boost Roche profits

Swiss drugs firm Roche has reported an 8% rise in annual sales, helped by sales of swine flu drug Tamiflu and cancer treatments, such as Herceptin.
The rate of growth is twice the industry average and operating profits were up by 14% to 15bn Swiss francs ($14.2bn, £8.89bn). 
However, overall net income for the year fell 22% to 8.5bn Swiss francs as a result of takeover costs. 
Last year, Roche bought US pharmaceutical giant Genentech. 
It says that this deal is already proving profitable. 
Although sales of Tamiflu soared last year, they are expected to fall sharply in 2010, to 1.2bn Swiss francs from 3.2bn Swiss francs in 2009.

Scientists Develop Cheaper Version Of Tamiflu

Tamiflu has emerged as one of the preferred weapons in the battle against flu, both seasonal and the H1N1 virus, but it has at least one drawback -- it tends to be costly.
But a group of scientists claim to have developed an alternative method for producing the active ingredient in Tamiflu. The new process could expand availability of the drug by reducing its cost, which now retails for as about $8 per dose. Their study is in ACS' Organic Letters, a bi-weekly journal.
Anqi Chen, Christina Chai and colleagues note that the global pandemic of H1N1 has resulted in millions of infected cases worldwide and nearly 10,000 deaths to date. Tamiflu, also known as oseltamivir phosphate, remains the most widely used antiviral drug for the prevention and treatment of H1N1 infections as well as bird flu and seasonal influenzas.
But growing demand for the drug has put pressure on the supply of shikimic acid, the raw material now used in making the drug.
"As a result, chemists worldwide including ourselves have explored the possibility of using other alternative raw materials for the synthesis of the drug," said Chen and Chai, who led the research.
The scientists describe a new process for making the drug that does not use shikimic acid. They found that D-ribose, a naturally-occurring sugar produced by fermentation in large scales, potentially provides an inexpensive and abundant source of starting material for making the drug. D-ribose costs only about one-sixth as much as shikimic acid.
In lab studies, the scientists demonstrated the potential use of D-ribose as an alternative source for the synthesis of Tamiflu.
Tamilflu is not a vaccine against flu, but rather an antiviral, used to treat effects of the flu. Patients who take Tamiflu after, or just before getting the flu reportedly have less severe symptoms and recover more quickly.
However, critics say Tamiflu is not nearly as effective against flu symptoms as its manufacturers claim.