PHILADELPHIA — In the midst of a shortage of pediatric strength oseltamivir, U.S. pediatric infectious disease experts have found that advised doses have been too low.
The best dosage of the anti-influenza drug for babies aged 9-11 months appears to be 3.5 mg/kg twice daily, while the best dosage for infants aged 0-8 months appears to be 3.0 mg/kg twice daily, according to pharmacokinetic results from 64 children.
Additionally, the Food and Drug Administration–approved dosage of oseltamivir (Tamiflu) for children aged 12-23 months (30 mg twice daily) resulted in blood levels of the active oseltamivir metabolite, oseltamivir carboxylate, that often were “lower than targeted” and hence a dosage of 3.5 mg/kg twice daily is now being evaluated by the research team, Dr. David W. Kimberlin said at the annual meeting of the Infectious Diseases Society of America.
“No safety concerns have been seen to date” testing oseltamivir in a total of 77 children less than 2 years old, said Dr. Kimberlin, professor of pediatrics at the University of Alabama, Birmingham.
The dosages for children younger than 1 year old recommended by Dr. Kimberlin and his associates are higher than currently recommended by the FDA and the Centers for Disease Control and Prevention under FDA emergency use authorization.
On Oct. 30, the FDA had authorized a dosage of 3.0 mg/kg for all infants younger than 12 months. The FDA prepared this amendment in mid-October, before the most recent data reported by Dr. Kimberlin were available, said Dr. Linda Lewis, medical team leader for the agency's division of antiviral drugs.
Dr. Kimberlin said in an interview that higher dosages are especially important for infants aged 9-11 months because they have been found to clear oseltamivir carboxylate significantly faster than younger children. Further, children aged 12-23 months show substantially faster clearance of the active metabolite than infants younger than 9 months, which is why the higher dosage of 3.5 mg/kg twice daily is being considered for the 12-23 month age group as well, Dr. Kimberlin added.
The Collaborative Antiviral Study Group, a multicenter U.S. research team funded by the National Institute of Allergy and Infectious Diseases, launched a study in January 2007 to collect pharmacokinetic data and determine the optimal oseltamivir dosage for children less than 2 years old.
The study began by looking at a dosage of 3.0 mg/kg twice daily, based on the FDA's prior approval of 30 mg twice daily in children 1-2 years old. The average weight of a 1-year-old child is 10 kg, which converts to a weight-based dosage of 3.0 mg/kg, Dr. Kimberlin explained.
The study sought to identify a dosage that produced a blood concentration with a 12-hour area under the curve of 3,800 ng•hr/mL, a level that resulted in the best efficacy plus no emergence of drug resistance in earlier studies. Investigators sought to avoid the level falling below 2,660 ng•hr/mL, where drug resistance has occurred, or rise above 7,700 ng•hr/mL, a level that might produce serious adverse events.
“It's a balance between an effective concentration and minimizing resistance from developing. Underdosing has more opportunity for resistance,” said Dr. Kimberlin, also codirector of the division of pediatric infectious diseases at Children's Hospital of Alabama, Birmingham. The 3.0 mg/kg twice daily dosage in infants aged 9-11 months led to blood levels falling below the 12-hour area under the curve minimum of 2,660 ng•hr/mL in 3 of 7 children, which led to raising the dosage to 3.5 mg/kg twice daily. The higher dosage produced no low level in any of five infants tested so far.
The study also showed that the 30 mg twice daily dosage for children aged 12-23 months led to levels falling below the specified minimum in 5 of 11 patients, which is why the 3.5 mg/kg twice daily dosage is now being studied. Dr. Kimberlin had no data yet for this part of the study. Among 23 children aged 9-23 months enrolled in the study, none had blood levels that exceeded the ceiling of 7,700 ng•hr/mL.
The remainder of the study group included 41 infants younger than 9 months. The 3.0 mg/kg twice daily dosage generally led to blood levels within the target range, with one infant having a level above the maximum, and three with levels below the target minimum.
Regarding the shortage of the antiviral, by late last month, the federal government had drained the Strategic National Stockpile of its remaining 234,000 doses of pediatric strength oseltamivir, Dr. Thomas R. Frieden, director of the Centers for Disease Control and Prevention reported at a press briefing last month.
The government is working closely with commercial pharmacy chains to supplement reserves by compounding adult doses into liquid, pediatric-strength oseltamivir.
“Please don't try this at home. This is something that should be done by a professional pharmacist,” said Dr. Frieden at the briefing.
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