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Janelle Vaughns

Few prescribing options exist for obese kids

Janelle Vaughns

“We are making progress in expanding the number of medicines with pediatric labeling, but we need to do more concerning providing dosing guidelines for children with obesity,” says Janelle D. Vaughns, M.D., director of bariatric anesthesia at Children’s National and the lead study author.

Despite years of study and numerous public health interventions, overweight and obesity continue to grow in the U.S. Currently, more than two-thirds of adults have these issues, according to data from the Centers for Disease Control and Prevention. Children and adolescents also are being affected at an increasing rate: About one in five is obese. Obesity and overweight have been linked with a bevy of health problems, including Type 2 diabetes, high blood pressure, coronary heart disease and stroke.

Additionally, because obesity increases the percentage of fat tissue in relation to lean tissue and enlarges kidney size, it can affect how readily the body takes up, metabolizes and excretes medicines.

This latter issue can be particularly problematic in children, a population for whom relatively few drug studies exist. Now, a study team that includes Children’s National Health System researchers suggests that, despite the U.S. Congress providing incentives to drug manufacturers to encourage the study of medications in children, few approved drugs include safe dosing information for obese kids.

The study, performed in conjunction with the Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research, surveyed pediatric medical and clinical pharmacology reviews under the FDA Amendments Act of 2007 and the FDA Safety and Innovation Act of 2012. The researchers used search terms related to weight and size to determine the current incorporation of obesity as a covariate in pediatric drug development.

Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only four labels, according to the study “Obesity and Pediatric Drug Development,” published online Jan. 19, 2018, in The Journal of Clinical Pharmacology.

“We are making progress in expanding the number of medicines with pediatric labeling, but we need to do more concerning providing dosing guidelines for children with obesity,” says Janelle D. Vaughns, M.D., director of bariatric anesthesia at Children’s National and the lead study author. “Moving forward, regulators, clinicians and the pharmaceutical industry should consider enrolling more obese patients in pediatric clinical trials to facilitate the safe and effective use of the next generation of medicines by obese children and adolescents.”

Study co-authors include Children’s Gastroenterologist Laurie Conklin, M.D., and Children’s Division Chief of Clinical Pharmacology Johannes N. van den Anker, M.D., Ph.D.; Ying Long, Pharm.D., University of Southern California; Panli Zheng, Pharm.D., University of North Carolina at Chapel Hill; Fahim Faruque, Pharm.D., University of Maryland; and Dionna Green, M.D., and Gilbert Burckart, Pharm.D., both of the FDA.

Research reported in this news release was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number 5T32HD087969.

Drug dosing guidelines poor fit for obese patients

Children’s National researchers are among the top teams examining how obesity alters pharmacokinetics and the effect of body mass index on drug dosing and treatment outcomes specifically for pediatric and adolescent patients.

Obesity affects about 12.7 million U.S. children and adolescents – or about 1 in 6 kids across the nation, according to the Centers for Disease Control and Prevention. Despite this, there is a significant dearth of dosing guidelines for practitioners, for example pediatric anesthesiologists, to follow when administering potent anesthetics to pediatric patients who are obese.

Janelle D. Vaughns, M.D., director of bariatric anesthesia within the Division of Anesthesiology, Pain and Perioperative Medicine, says Children’s National Health System sees pediatric and adolescent patients of extreme weight (as much as 450 pounds) presenting for weight-loss surgery. In order to ensure that patients remain anesthetized during their surgical procedures, anesthesiologists use various classes of drugs, including hypnotics, muscle relaxants and pain medications. Dr. Vaughns says providers across the nation face similar challenges when determining accurate and precise dosing of drugs for obese pediatric patients.

“Medical guidelines calibrated for a 13-year-old of typical weight cannot be applied to a 13-year-old who weighs 400 pounds. Because morbid obesity in kids is a relatively new phenomenon in our country and globally, there are no formal guidelines to aid with dosing. In this scenario, most doctors extrapolate from guidelines written for lean patients. Because anesthetic drugs are so strong, it is essential to use the correct dose in all patients,” she says.

A recent brief report that Dr. Vaughns co-authored examines this issue. Researchers at Children’s National and the Washington Hospital Center conducted a retrospective review for 440 adult patients who received rapid sequence endotracheal intubation (RSI) in an urban, tertiary care academic Emergency Department. The patients received succinylcholine (a muscle relaxant) and etomidate (a short-acting anesthetic), whose doses are ideally calculated in milligrams per kilogram of total body weight.

The work, published in the December 2016 issue of American Journal of Emergency Medicine, reinforced the importance of data-driven guidelines for all patients. The research team found that the 129 obese patients included in the study were more likely to receive too little of the studied drugs while the 311 non-obese patients studied were more likely to receive too much medicine.

“Our single-center study demonstrates that obesity is a significant risk factor for underdosing RSI medications, whereas non-obesity is a risk factor for overdosing of these medications,” the research team concludes. This study also was reviewed and featured by the New England Journal of Medicine “Journal Watch” in October 2016.

Broadly, the issue of dosing potent medicines for pediatric obese patients is a national public health concern, Dr. Vaughns says. Research teams across the nation have made a concerted effort to publish papers on topics such as how obesity alters pharmacokinetics – how the body takes up, distributes and disposes of powerful medicines – and the deleterious effect of unhealthy body mass index on treatment outcomes for children with diseases such as acute myeloid leukemia.

Dr. Vaughns is among the clinician researchers working with the Pediatric Trials Network (PTN), sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, to fill this research gap. Working as a team, she, Evan Nadler, M.D., a bariatric surgeon, and Johannes N. van den Anker, M.D., Ph.D., division chief of Clinical Pharmacology, enroll pediatric patients in ongoing trials with a special focus on surgical patients who are obese.

The network is currently conducting pediatric studies at a number of locations, including Children’s National, leveraging blood samples and other specimens drawn during regular care to better understand how medicines routinely used in pediatric patients actually work in kids and to determine appropriate dosing.

Ultimately, the information PTN researchers discover from their multi-year studies will help the Food and Drug Administration update medicine labels to reflect safer, more accurate and more effective dosing for all pediatric patients.