title: Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis.
abstract: 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.
  
  
  METHODS
  Open-label, nonrandomized, sequential, 2-part study conducted in 11 medical centers in the United States and United Kingdom.
  
  
  METHODS
  Eighty-three pediatric patients with severe sepsis aged term newborn (>or=38 weeks' gestation) to <18 years old.
  
  
  METHODS
  In part 1, drotrecogin alfa (activated) was administered as escalating doses of 6, 12, 24, and 36 micro g/kg per hour for 6 hours for each patient (n = 21). In part 2, drotrecogin alfa (activated) was infused at a rate of 24 micro g/kg per hour for 96 hours in 62 patients.
  
  
  METHODS
  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 (>or=38 weeks' gestation) to <18 years. In part 1, a dose of 24 micro g/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 micro g/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.
authors.affiliation: Department of Pediatrics, Division of Pediatric Critical Care, Children's Hospital at Saint Francis, Tulsa, Oklahoma, USA.
authors.forename: Phil
authors.initials: P
authors.lastname: Barton
authors.forename: Andre C
authors.initials: AC
authors.lastname: Kalil
authors.forename: Simon
authors.initials: S
authors.lastname: Nadel
authors.forename: Brahm
authors.initials: B
authors.lastname: Goldstein
authors.forename: Regina
authors.initials: R
authors.lastname: Okhuysen-Cawley
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Brilli
authors.forename: Jeanne S
authors.initials: JS
authors.lastname: Takano
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: Quint
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Yeh
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Dalton
authors.forename: Morris R
authors.initials: MR
authors.lastname: Gessouron
authors.forename: Kellie E
authors.initials: KE
authors.lastname: Brown
authors.forename: Helen
authors.initials: H
authors.lastname: Betts
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: William L
authors.initials: WL
authors.lastname: Macias
authors.forename: David S
authors.initials: DS
authors.lastname: Small
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Wyss
authors.forename: Becky M
authors.initials: BM
authors.lastname: Bates
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Utterback
authors.forename: Brett P
authors.initials: BP
authors.lastname: Giroir
mesh_terms: D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000991:Antithrombins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011486:Protein C / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D020151:Protein C Deficiency / Q000188:drug therapy; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D012720:Severity of Illness Index
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000991:Antithrombins; D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D011486:Protein C; D011994:Recombinant Proteins; C036309:fibrin fragment D; C421124:drotrecogin alfa activated