New study aims to clarify dosing information for drug used to treat
The Pediatric Trials Network (PTN) has launched a clinical study designed to test the effects of the antiviral drug acyclovir in premature infants infected with the herpes simplex virus (HSV). The study is expected to enroll its first patient this month.
Most neonatal herpes infections occur at birth. Infants are exposed to the virus in the genital tract of mothers, many of whom are unaware that they are HSV-positive. Occurring in approximately 60 per 100,000 live births, neonatal HSV can have devastating consequences. Untreated, it has a mortality rate of up to 60 percent. Even with treatment, it can cause epilepsy, blindness, cognitive abnormalities, and other considerable disabilities among survivors.
Acyclovir is given to babies suspected of having HSV. Possible symptoms include lesions on the skin, eyes, or mouth; lethargy; or multiple organ dysfunction. Because of the high mortality and morbidity associated with the infection, most physicians prescribe acyclovir even before laboratory test results come back and a firm diagnosis of HSV is made. Thus, thousands of babies, most of whom turn out to be HSV-negative, receive acyclovir each year.
'Ballpark dosing' in children
In spite of acyclovir’s widespread use in infants, there are virtually no data on how much drug should be administered or how often. It was only in 1998 that the FDA began requiring drug developers to conduct pediatric trials of medications that might be prescribed for children. However, this requirement does not apply to generic drugs like acyclovir because pharmaceutical companies have no exclusive right to market them.
The result is guesswork. Doctors currently refer to multiple sources, such as the American Academy of Pediatrics’ (AAP) Red Book and the NeoFax manual, to help them decide what dose to use. However, dosage recommendations vary, and very few are supported by data from clinical trials in children.
“The pediatric dose is often just extrapolated from the adult dose,” said P. Brian Smith, MD, MPH, associate professor of pediatrics and principal investigator of the PTN acyclovir study. “For example, if the adult dose is 140 mg, then the pediatric dose may be estimated at 2 mg/kg. But when we actually bother to study the effect of a drug on kids, we often find that the extrapolated dose results in either over- or underdosing.”
This is because children and adults metabolize and eliminate drugs from the body in different ways and at different rates. Even among children of similar age, there is still a lot of variability when it comes to drug metabolism.
“If you give an ‘average’ dose to two newborns, both of whom were delivered after 32 weeks in the womb and both 7 days old, one is liable to have a trough level of 2 ug/ml
(micrograms per milliliter), and the other a trough level of 20 or 25 ug/ml. Some babies will be fine, but babies who have low levels, they are not getting enough drug,” said Danny Benjamin, MD, PhD, MPH, professor of pediatrics and faculty associate director of the Duke Clinical Research Institute.
“Obviously, underdosing an antiviral is a big problem when you’re dealing with a virus that is associated with a 60 percent mortality rate,” said Smith. “Overdosing, on the other hand, may cause side effects while offering no added benefit. We’re doing this study to find out what the optimal dose is.”
Standard reference for physicians
Smith’s team will enroll 20 premature babies suspected of having HSV from neonatal ICUs at Tulane Medical Center in New Orleans, LA, Wesley Medical Center in Wichita, KS, and Duke University Medical Center in Durham, NC. The babies will be assigned to three groups depending on their gestational age (i.e., the time they spent in the womb) and chronological age. The first group will comprise babies with a gestational age of 29 weeks and a chronological age of 1–14 days; the second, babies with a gestational age of 23–29 weeks and a chronological age of 14–44 days; and the third, babies with a gestational age of 30–34 weeks and a chronological age of 45 days or fewer. A normal pregnancy lasts anywhere from 38 to 42 weeks.
Over the course of 3 days, Smith’s team will give each infant 3–5 doses of acyclovir. They will also draw 200 uL (microliters) of blood seven times, for a total of about one-third of a teaspoon. These samples will be tested and the data analyzed to understand the drug’s pharmacokinetics (PK)—i.e., what the body does to it, such as how it absorbs it or metabolizes it. Using this information, the team will identify the optimal dose of acyclovir for each group of infants.
Especially instrumental in designing the acyclovir study has been the PTN’s core group of experts in pharmacometrics—a discipline that uses pharmacological and physiological models to quantitatively analyze how drugs and patients interact. “[Our] team has simulated and designed the most appropriate dose to [test] in premature infants according to their degree of prematurity as well as chronological age,” said Michael Cohen-Wolkowiez, MD, assistant professor of pediatrics and a member of the PTN’s pharmacometrics group.
“We also determined the minimum number and most appropriate times to draw blood samples for PK analysis. This is important in premature infants because the number of samples that can be obtained for a study is very limited. By performing simulations and PK/PD modeling during the study design phase, we can increase the chances of a finding the most effective and safest dose of acyclovir for this vulnerable population,” Cohen-Wolkowiez added. PD, or pharmacodynamics, is the opposite of PK; it looks at how a drug affects the body.
“Mini” drug development programs
Smith’s team plans to submit their findings to the FDA, which could result in dosing information for premature infants being added to acyclovir’s label. “The new FDA label can be used as a standard reference for clinicians the next time they need to treat a premature baby with acyclovir,” said Smith. “We also hope that other resources used by clinicians and pharmacists to dose medication, such as the AAP Red Book and the NeoFax manual, will incorporate the new data into their publications.”
The acyclovir study is only one of 32 studies that the PTN is planning to conduct. In September 2010, the National Institutes of Health awarded a $95 million grant to a team led by Benjamin to run the PTN and conduct pediatric clinical trials for 16 generic drugs over the next 5 years. “I hope we double that number,” Benjamin said.
The PTN functions as an infrastructure for conducting safe and scientifically rigorous pediatric trials. In a massive effort that Benjamin likens to “multiple mini drug development programs,” the PTN will study product formulation, drug dose and safety, and device development. It will then use data collected from the trials to inform pediatric drug labeling and to provide regulators, pediatricians, and researchers with new information about how children respond to medication. The primary goal is to generate the data needed to produce evidence-based clinical practice guidelines that clinicians can use when treating children.
The PTN comprises six groups dedicated to the following activities: 1) clinical operations and program management; 2) the clinical pharmacology design components of trials, formulations, and pharmacogenomics; 3) pharmacokinetic and pharmacodynamic simulations, analysis, and modeling; 4) common safety reporting across trials and an ethics review of each protocol; 5) overseeing collaborations in the multi-disciplinary development of devices for use in children; and 6) training the next generation of clinical pharmacologists and clinical trialists.
The network plans to launch four more clinical trials this year. A study of metronidazole, an antibiotic commonly given to babies with necrotizing enterocolitis—a condition that can bore a hole in their intestines, allowing bacteria to leak out into the abdomen—is already underway.
Publication list of Werner Brannath A) Original papers in Statistics and Mathematics published in peer-reviewed journals Gutjahr G, Brannath W, Bauer P, (2010). A general approach to the conditional error rate principle with nuisance parameters. Biometrics, accepted. Brannath W and Bretz F (2010). Shortcuts for locally consonant closed test procedures. Journal of the American Statistical
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