Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis.
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.
Barton
Phil
P
Department of Pediatrics, Division of Pediatric Critical Care, Children's Hospital at Saint Francis, Tulsa, Oklahoma, USA.
Kalil
Andre C
AC
Nadel
Simon
S
Goldstein
Brahm
B
Okhuysen-Cawley
Regina
R
Brilli
Richard J
RJ
Takano
Jeanne S
JS
Martin
Lynn D
LD
Quint
Peter
P
Yeh
Timothy S
TS
Dalton
Heidi J
HJ
Gessouron
Morris R
MR
Brown
Kellie E
KE
Betts
Helen
H
Levin
Michael
M
Macias
William L
WL
Small
David S
DS
Wyss
Virginia L
VL
Bates
Becky M
BM
Utterback
Barbara G
BG
Giroir
Brett P
BP
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
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