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Safety, Pharmacokinetics, and Pharmacodynamics of Drotrecogin Alfa (Activated) in Children With Severe Sepsis

Phil Barton, MD^*, Andre C. Kalil, MD, Simon Nadel, MRCP, MBMS, Brahm Goldstein, MD^||, Regina Okhuysen-Cawley, MD^¶, Richard J. Brilli, MD^#, Jeanne S. Takano, MD^**, Lynn D. Martin, MD, Peter Quint, MD, Timothy S. Yeh, MD^||||, Heidi J. Dalton, MD^¶¶, Morris R. Gessouron, MD^##, Kellie E. Brown, RN, BSN^*, Helen Betts, RSCN, Michael Levin, MBBCh, FRCP, PhD, William L. Macias, MD, PhD^***, David S. Small, PhD^***, Virginia L. Wyss, BS^***, Becky M. Bates, MS^***, Barbara G. Utterback, MS, MBA^*** and Brett P. Giroir, MD^**

^* Department of Pediatrics, Division of Pediatric Critical Care, Children’s Hospital at Saint Francis, Tulsa, Oklahoma
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Department of Paediatrics, Imperial College School of Medicine at St. Mary’s Hospital, London, United Kingdom
^|| Division of Pediatric Critical Care, Oregon Health Sciences University, Portland, Oregon
^¶ Pediatric Critical Care Section, Baylor College of Medicine, Houston, Texas
^# Division of Critical Care Medicine, Children’s Hospital Medical Center, Cincinnati, Ohio
^** Department of Pediatrics, Division of Pediatric Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas
Department of Anesthesiology, Children’s Hospital and Regional Medical Center, Seattle, Washington
Emmanuel Hospital and Health Center, Portland, Oregon
^|||| Children’s Hospital Oakland, Oakland, California
^¶¶ Children’s National Medical Center, Washington, District of Columbia
^## Critical Care Medical Section, Children’s Hospital of Oklahoma, Oklahoma City, Oklahoma
^*** Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

Objective. In a phase 3 trial, recombinant human activated protein C (drotrecogin alfa [activated]) significantly reduced mortality in adult patients with severe sepsis. We have now performed a preliminary analysis of the safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in pediatric patients with severe sepsis.

Design and Setting. Open-label, nonrandomized, sequential, 2-part study conducted in 11 medical centers in the United States and United Kingdom.

Patients. Eighty-three pediatric patients with severe sepsis aged term newborn (38 weeks’ gestation) to <18 years old.

Intervention. In part 1, drotrecogin alfa (activated) was administered as escalating doses of 6, 12, 24, and 36 µg/kg per hour for 6 hours for each patient (n = 21). In part 2, drotrecogin alfa (activated) was infused at a rate of 24 µg/kg per hour for 96 hours in 62 patients.

Main Outcome Measures. Plasma clearance, plasma concentration, D-dimer, protein C, and antithrombin levels were measured, and adverse events were monitored.

Results. The trial enrolled 83 pediatric patients with severe sepsis, aged term newborn (38 weeks’ gestation) to <18 years. In part 1, a dose of 24 µg/kg per hour produced steady-state plasma concentrations of activated protein C similar to those attained in equivalently dosed adult severe sepsis patients. For all pediatric patients dosed at 24 µg/kg per hour, the median weight-normalized clearance was 0.45 L/hour/kg and the median steady-state concentration was 51.3 ng/mL. The mean plasma half-life was 30 minutes. Weight-normalized clearance in pediatric and adult patients did not differ significantly with age or weight. D-dimer levels decreased 26% from baseline to end of infusion. Baseline levels of protein C and antithrombin increased 79% and 24%, respectively, over the 96-hour treatment period in part 2. The incidence of serious bleeding during infusion and during the entire study period was 2.4% and 4.8%, respectively.

Conclusions. Pediatric patients with severe sepsis manifest sepsis-induced coagulopathy including protein C deficiency comparable to that seen in adults with severe sepsis. The pharmacokinetics, pharmacodynamic effects, and safety profile of drotrecogin alfa (activated) in pediatric patients are similar to those previously published for adult patients. A large, phase 3, randomized, placebo-controlled study is ongoing to confirm these results and formally assess the safety and efficacy of drotrecogin alfa (activated) in children.

Key Words: drotrecogin alfa (activated) • activated protein C • Xigris • sepsis • pediatric

Abbreviations: SIRS, systemic inflammatory response syndrome • ICH, intracranial hemorrhage • C_ss, steady-state plasma concentration • PIM, pediatric index of mortality • Cl_p, plasma clearance • CV, coefficient of variation

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