The FDA approved Drotrecogin alfa (activated) [DrotAA] for the reduction of mortality in adult patients with severe sepsis [sepsis with acute organ dysfunction] and a high risk of death (e.g. APACHE II score ≥25). In PROWESS, a Phase III clinical trial, limited supplies of DrotAA necessitated excluding patients whose actual body weight was >135 kg. The primary objective of this open label, Phase 4 trial was to compare the exposure to DrotAA in severe sepsis patients at high risk of death who weighed >135 kg to those who weighed <<26>135 kg. A secondary purpose was to quantify the elimination half-life of DrotAA in severe sepsis patients.
PROWESS inclusion/exclusion criteria were used, except patients >135 kg were also enrolled. Blood samples were taken for DrotAA steady state concentration analysis once each day and for elimination half-life analysis at 0, 15, 30, 45, 60, 90, and 120 minutes after terminating the infusion. DrotAA activity was assayed at a central laboratory. Weight-normalized clearance of DrotAA was calculated and values for patients weighing <<26>135 kg were compared with those >135 kg.
Patient weight range was 59 kg –227 kg. Of 52 patients enrolled, 32 weighed <<26>135 kg, 12 weighed 136-159 kg, and 8 weighed >160 kg.
There is no statistically significant difference in steady-state concentrations or elimination half-life of DrotAA in patients <<26>135 kg and >135 kg.
Dosing of DrotAA should be based on actual body weight. ≤135 kg>135 kgP-valueN3220Mean weight (kg) [range]93 [59-133]158 [137-227]P=<0.001Mean BMI [range]33 [22-59]59 [41-75]P=<0.001DrotAA steady-state concentration (ng/mL) [interquartile range]60.2 [48.1-72.4]65.5 [49.9-81.0]P=0.5995DrotAA half-life (minutes) [interquartile range]19.1 [15.3-23.0]16.7 [12.2-21.1]P=0.3960
H. Levy, Eli Lilly and Company