PEDIATRICS Vol. 113 No. 1 January 2004, pp. 134
Safety, Pharmacokinetics, and Pharmacodynamics of Drotrecogin Alfa (Activated) in Children With Severe Sepsis
Karen D. Weiss, MD
Office of Drug Evaluation VI
Office of New Drugs
Center for Drug Evaluation and Research
Food and Drug Administration
Rockville, MD 20852
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II
In 1994, the Food and Drug Administration issued a regulation for labeling drugs and biologicals for pediatric use. Known as the "pediatric rule," it permits the Food and Drug Administration to label a product for a pediatric disease based on efficacy findings in adults. This extrapolation of efficacy from adult data are limited to situations in which the disease is similar and the drug behaves in a similar manner (ie, the pharmacokinetic, pharmacodynamic, and/or side-effect profile) in adults and children.
Barton et al1 describe results of a nonrandomized, dose-finding study of drotrecogin alfa in 83 pediatric patients with sepsis. Over the age range of pediatric patients studied (term newborn to 18 years), drotrecogin alfa at the dose and schedule used in the efficacy trial in adults (PROWESS)2 yielded similar pharmacokinetic profiles, effects on D-dimer levels, other coagulation parameters, and bleeding rates as that seen in adults. Despite the limited numbers of children studied, these data seem to satisfy one of the two criteria for application of the pediatric rule. However, baseline differences between PROWESS and this pediatric study raise questions about whether pediatric sepsis is sufficiently similar to adult sepsis. In PROWESS, the most common site of infection was the lung; in the pediatric study, it was the blood. In PROWESS, rates of Gram-negative and Gram-positive infections were similar, whereas in the pediatric study, the proportion of Gram-negative infections was almost twice the Gram-positive rate. Although subgroup analyses of the PROWESS data set suggested that the drotrecogin alfa treatment effect was present across most subgroups, one notable exception was the subgroup analysis based on baseline Acute Physiology and Chronic Health Evaluation (APACHE II) quartile. APACHE II is a predictor of risk of mortality in adult patients with sepsis. In PROWESS, only patients with baseline APACHE II scores above the median 
25) experienced the drotrecogin alfa mortality benefit. Those in the first APACHE II quartile, ie, at the lowest risk of death from their sepsis, had slightly higher 28-day mortality if they received drotrecogin alfa.3 In this pediatric study, overall mortality was 10%. This raises questions about whether pediatric patients who receive drotrecogin alfa will respond similarly to the PROWESS patients in the higher APACHE II quartiles or those in the lowest APACHE II quartile. The ongoing randomized, controlled, pediatric trial is designed to answer that question.
Drotrecogin alfa is the first biological therapy approved for sepsis. The fact that we do not yet know whether it will reduce mortality and morbidity in pediatric sepsis 2 years after its approval for adults reflects the conservative approach to the study of new therapies in vulnerable populations. Drugs and biological therapies under evaluation for a disease that affects both adults and children are usually tested in adults first, invariably leading to a lag in knowledge about the drug in children. Key questions for pediatric development relative to the adult studies include whether, when, and how to study the drug or biological in the pediatric population. Knowledge gained from adult studies such as PROWESS can help inform such decisions. The adult efficacy studies do not need to be completed before initiating pediatric studies, as was the case here. The PROWESS study results highlight the difficulties in application of the pediatric rule in sepsis. There is still much to understand about sepsis and factors that affect outcome in children and adults.
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FOOTNOTES
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Received for publication Oct 24, 2003; Accepted Oct 24, 2003.
Address correspondence to Karen D. Weiss, MD, Food and Drug Administration, 1401 Rockville Pike, Ste 380, Rockville, MD 20852. E-mail: weissk{at}cber.fda.gov
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REFERENCES
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- Barton P, Kalil AC, Nadel S, et al. Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis.
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- Food and Drug Administration. Product approval information–licensing action. Available at: www.fda.gov/cder/biologics/products/droteli112101.htm. Accessed November 20, 2003
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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