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 (greater than or equal to38 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 (&GE;38 weeks' gestation) to <18 years. In part 1, a dose of 24 mug/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 mug/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.