Drotrecogin alfa (activated) in patients with severe sepsis presenting with purpura fulminans, meningitis, or meningococcal disease: a retrospective analysis of patients enrolled in recent clinical studies.

INTRODUCTION: We report data from adult and pediatric patients with severe sepsis from studies evaluating drotrecogin alfa (activated) (DrotAA) and presenting with purpura fulminans (PF), meningitis (MEN), or meningococcal disease (MD) (PF/MEN/MD). Such conditions may be associated with an increased bleeding risk but occur in a relatively small proportion of patients presenting with severe sepsis; pooling data across clinical trials provides an opportunity for improving the characterization of outcomes. METHODS: A retrospective analysis of placebo-controlled, open-label, and compassionate-use trials was conducted. Adult patients received infusions of either DrotAA or placebo. All pediatric patients (<18 years old) received DrotAA. 189 adult and 121 pediatric patients presented with PF/MEN/MD. RESULTS: Fewer adult patients with PF/MEN/MD met cardiovascular (68.3% versus 78.8%) or respiratory (57.8% versus 80.5%) organ dysfunction entry criteria than those without. DrotAA-treated adult patients with PF/MEN/MD (n = 163) had an observed 28-day mortality rate of 19.0%, a 28-day serious bleeding event (SBE) rate of 6.1%, and an intracranial hemorrhage (ICH) rate of 4.3%. Six of the seven ICHs occurred in patients with MEN (three of whom were more than 65 years old with a history of hypertension). DrotAA-treated adult patients without PF/MEN/MD (n = 3,088) had an observed 28-day mortality rate of 25.5%, a 28-day SBE rate of 5.8%, and an ICH rate of 1.0%. In contrast, a greater number of pediatric patients with PF/MEN/MD met the cardiovascular organ dysfunction entry criterion (93.5% versus 82.5%) than those without. DrotAA-treated PF/MEN/MD pediatric patients (n = 119) had a 14-day mortality rate of 10.1%, an SBE rate of 5.9%, and an ICH rate of 2.5%. DrotAA-treated pediatric patients without PF/MEN/MD (n = 142) had a 14-day mortality rate of 14.1%, an SBE rate of 9.2%, and an ICH rate of 3.5%. CONCLUSION: DrotAA-treated adult patients with severe sepsis presenting with PF/MEN/MD had a similar SBE rate, a lower observed 28-day mortality rate, and a higher observed rate of ICH than DrotAA-treated patients without PF/MEN/MD. DrotAA-treated pediatric patients with severe sepsis with PF/MEN/MD may differ from adults, because all three outcome rates (SBE, mortality, and ICH) were lower in pediatric patients with PF/MEN/MD.

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. 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 (>or=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 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. 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 (>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.