by JJ Bhongsatiern
When the father of a baby girl told me of the recent death of his daughter, he spoke of his great pain and confusion. His recently born (newborn) daughter had been prescribed a codeine-containing cough medicine of the same type that previously had been helpful to the father when he had a cough. This tragic difference in outcomes for the two family members emphasizes how important it is for medication to be age-specific and asks the question as to how can we develop safer new drugs or drug doses better suited for children and, in particular, for newborns?
In the past ten years, an attempt to develop an age-specific medication for children, including newborns has been undertaken by the FDA. Unfortunately, findings from a study led by William Rodriguez of the US food and drug administration showed that only a handful of newborns hospitalized between 1997 and 2010 in the U.S. received medicines with FDA-approved labels. Most medicines used were off-label, an established way for doctors to give medicines to newborns when no information on drug safety and efficacy has been established for their age group. This is a questionable approach if newborn patients, already vulnerable by their own fragile nature, are at risk of being treated with medicines that may do more harm than good.
Newborns, infants up to 28 days after birth, not only have an extremely small body size but other significantly different attributes, such as body composition growth and maturation, which affect the medicines they can tolerate. Growth and maturation describe the process of developmental changes in body size and organ functions in newborns. An average adult’s weight is 60% body water and 20% fat, whereas a newborn’s body is comprised of 80-85% water and 5-10% fat, respectively. Liver and kidney functions are less developed in newborns. Some liver enzymes are low during the first two months and reach the adult level during the first couple years of life, whereas other enzymes are abundant after birth but undetectable in adults. In the kidney, the filtration process has been shown to increase in the first year of life and reach adult levels by 6 to 12 months of age.
Given that newborns are different from adults and older children and are thus prone to sometimes catastrophic reactions to drugs readily tolerated by those older age groups, there is a pressing need to develop age-specific medications for newborns that take into account their distinctive growth and maturation. Although this serious healthcare and drug development issue is now well recognized, the drug development process needed to address it is not an easy path. It is a long and costly process to develop new medicines, with approximately 10-15 years typically required for one drug to ultimately pass all of the tests to be approved (see figure 2). During the so-called phase 1-3 clinical trials, thousands of volunteers are recruited to be subjects so that more information of drug efficacy and safety can be studied. Unfortunately, the volunteers are typically adults aged 18-60 years, not newborns.
Clinical studies in newborns remain challenging because of ethical and practical constraints. Enrollment is usually low in most newborn studies because of the difficulty in obtaining consent or permission from the parents. Moreover, generally no more than 3 ml/kg (1-5%) of total blood volume is recommended to be drawn from a child within a 24 hour period. These two factors have resulted in sparse data from clinical research on newborns, making it difficult to achieve label approval.
To improve clinical studies on newborns, an approach of modeling and simulation is being recognized by the FDA and pharmaceutical industries as a useful tool to enhance clinical research with limited data. The primary goal is to improve the design of studies and data analyses to help with making decisions about clinical studies in children. For example, by using information available from adults, a simulation might help predict whether children and adults might have a similar response to a drug. Other simulations might help find reasons why drugs are distributed in a different manner throughout the body in adults compared to newborns. Ultimately these models help to make sense of the small data sets of studies on newborns. By means of example, recently, a proposal was made to the FDA to conduct clinical studies to seek approval for heart medication for children, medication that is already in use to treat adults with abnormal heart rhythms. The researchers argued that similar responses to the drug had been found in both children and adults. Only children aged 2 years and older were recruited for the studies and the researchers proposed to extrapolate dosing recommendations for younger ages based merely on body size differences. The FDA found this unsatisfactory and sought more specific dosing recommendations for newborns and infants. In this case, computer modeling and simulation approaches were utilized to achieve those desired dosing recommendations. The model findings suggested that an age factor should be included in dosing recommendations for children less than 2 years of age, including newborns, due to maturation events in kidney function. The model also confirmed that it is appropriate to use only body size as a factor in the drug dose for children aged 2 years and older (see figure 3).
In summary, the integration of scientific knowledge, clinical data, and information technology is now helping drug developers to understand and connect the pieces to develop better medications for newborns. With modeling and simulation approaches, a more effective foothold in drug development in newborns is finally being established. Incorporation of available information from adults and older children will ensure successful clinical studies to support the development of age-specific medications in newborns. All of these focused approaches should make it less likely that the babies of future generations will face the tragic outcomes suffered by too many babies in recent decades.
JJ Bhongsatiern is a 2009 fellow of the Fulbright Science and Technology Award program, from Thailand, and a PhD candidate in Pediatric Clinical Pharmacology and Pharmacometrics at University of Cincinnati.
The March edition of TGS magazine was guest edited by Puripant Ruchikachorn, a 2010 fellow of the Fulbright Science & Technology Award, from Thailand, and a PhD Candidate in Computer Science at Stony Brook University.