Obesity does not alter the pharmacokinetics of drotrecogin alfa (activated) in severe sepsis

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was > 135 kg were excluded from the Phase III PROWESS trial. OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing > 135 kg with those weighing less than or equal to 135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t(1/2)) of DrotAA in these patients. METHODS: PROWESS inclusion/exclusion criteria were used, except that patients > 135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (C-ss) analysis of activated protein C once each day and for t(1/2) analysis after infusion. Weight-normalized clearance (CIp) and t(1/2) estimates for DrotAA were calculated and compared between weight groups. RESULTS: Patient weight range was 59-227 kg. There were 32 patients less than or equal to 135 kg and 20 patients > 135 kg enrolled. Median CIp was 0.45 L/h/kg (interquartile range [IQR] 0.37-0.54) for patients less than or equal to 135 kg and 0.42 L/h/kg (IQR 0.33-0.54) for patients > 135 kg (p = 0.692). Median estimates of C-ss were 51.9 ng/mL (IQR 43.4-62.0) and 56.5 ng/mL (IQR 44.9-71.1; p = 0.570). In patients less than or equal to 135 kg, DrotAA had a median t(1/2) of 16.7 minutes (IQR 13.9-20.0) compared with 16.0 minutes (IQR 12.9-19.8) in patients > 135 kg (p 0.767), for a composite median t(1/2) of 16.3 minutes (IQR 14.2-18.8). CONCLUSIONS: There is no statistically significant difference in C-ss concentrations or t(1/2) of DrotAA between patients weighing less than or equal to 135 kg and > 135 kg. DrotAA should be dosed by actual body weight.