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When it comes to pediatric therapy, children ?are not just small adults.? This was one of the dominant messages emerging from the recent National Institutes of Health, Division of AIDS, Forum to Promote TRIUMPH ? TB Research in Underserved Maternal and Pediatric Populations with HIV.
When it comes to pediatric therapy, children “are not just small adults.” This was one of the dominant messages emerging from the recent National Institutes of Health, Division of AIDS, Forum to Promote TRIUMPH – TB Research in Underserved Maternal and Pediatric Populations with HIV. More than 200 participants convened in Washington, D.C., to discuss the diagnosis, medication, and treatment of women and children co-infected with TB and HIV. But the presenters made clear that the problems in treating children extend to all therapeutic areas-in both developed countries and those with limited resources.
Drug formulation dilemmas
Gene Morse, PharmD, professor of pharmacy practice at the University of Buffalo, Center of Excellence in Bioinformatics and Life Sciences, Buffalo, N.Y., said that there are very few medicines developed specifically for children. Dr Morse, who has been working in the field of HIV drug development since the inception of the first drugs more than 2 decades ago, said that manufacturer drug formulation and drug chemistry play a significant role.
Typically, drugs are developed and approved for adult formulation and “there is very little pressure of how you would use it for kids,” he said. For example, if a company develops a new product with a dose of 200 mg, “you may be able to make a 200-mg tablet or capsule, but not a 100-mg or 25-mg dose,” which Dr Morse explained, “would be potentially suitable for child dosing.” This makes dosing an exercise of scoring pills into halves or smaller, crushing them to mix with palatable juices, and/or foods, or other guesswork that can severely compromise drug bioavailability.
The pharmacokinetic (PK) effect of drugs given to children also is influenced by the child’s individual metabolism and physical status. Dr Morse said malnutrition, problems with the kidneys, liver, or the GI tract will affect drug absorption and may result in adverse events.
While malnutrition is rare in developed countries, Dr Morse said childhood obesity--at alarming levels in the United States-now is affecting pediatric dosing with a new set of problems. Studies have shown that an increase in fatty tissue and organ mass size affects the distribution, metabolism, and excretion of the drug, and highly liphophilic drugs for example, may require a much larger dose.
The problem with age-weight bands
Pediatrician Rachel Vreeman, MD, MS, assistant professor of pediatrics, Children’s Health Services Research at Indiana University School of Medicine, Indianapolis, describes how therapies for children have traditionally been guided by age-weight bands.
“We typically have tried to come up with a dose for children that is a certain number of milligrams per kilogram of body weight of the child. It is from these calculations that the weight bands come from-they simplify the mg/kg dosing and the math.” But this objective calculation precludes individual differences.
As co-director of the University’s research program in Kenya, Dr Vreeman recently has completed a PK study of nevirapine, a non-nucleoside reverse transcriptase inhibitor, to learn more about pediatric therapy among Kenyan children.
She found that as body weight increased, this increased total body water which increased clearance, and this, “suggests that we might need to use lower doses,” than what the standard age-weight charts recommend.
Dr Vreeman explained that drug metabolism is also affected by discrete growth stages.
“At various ages in a child’s growth, their liver and kidney process drugs differently, and how well they process varies from when they are a baby, a toddler, in grade school, and into adolescence.” Nonetheless, the usual scenario for a clinician is “to give a very malnourished teenager the same dose as a pudgy 5-year-old if the 2 children weigh the same amount,” she said.
While in general, said Dr Morse, “the area of pediatrics is underrepresented in a lot of pharmacy schools,” more student exposure to this subspecialty would increase awareness to pediatric medicine needs. “We also need to have a reimbursement system that spends time on education and people to help monitor adherence,” he added, emphasizing children must rely on adults or caregivers to dispense medicines on time and as prescribed.
Dr Vreeman’s wish list for better adherence includes developing novel drug delivery such as aerosols, dissolving films, or wafers that don’t require swallowing a (broken) pill or taking unpleasant syrups--both subject to inaccurate measurement.
Changes in FDA regulations in the last decade has improved the odds for pediatric research, but less than one-third of approved drugs have been labeled for use in children. The agency can require a company to engage in these studies if it determines the product will be used in a substantial number of children, however, studies must be done in children who have the illness or condition the drug will affect. As children cannot consent, participate, and report on their own, pediatric trials are a daunting ethical and clinical prospect to the development process.
On September 15, 2010, FDA announced a drug safety alert that further underscores the need for individualized pediatric dosing. Children receiving Valganciclovir hydrochloride (Valcyte R), an antiviral indicated for post-transplant patients, were found to be at risk for overdosing if they have low body weight, low body surface area, and below-normal serum creatinine. The current labeling advises strict adherence to avoid overdosing and reports safety and efficacy in pediatric patients has not been established. Adverse events may include anemia and the drug was found to be mutagenic and carcinogenic in animal studies.
“In this country it’s shocking when we look at the literature. The guidelines for dosing ear infections, reflux, asthma medications, or diabetes-in all of those cases we are very often relying on adult information that has not been tested well,” Dr Vreeman said.
“Without careful testing in children to see how they process, we really are just guessing.”