• Howard Levy, David Small, Darell E Heiselman, Richard Riker, Jay Steingrub, Ruqin Chen, Rebecca L Qualy, Christelle Darstein, and Ellen Mongan.
• Acute Care, US Medical Division, Eli Lilly and Company, Indianapolis, IN 46285, USA. hlevy@lilly.com
• Ann Pharmacother. 2005 Feb 1; 39 (2): 262-7.

BackgroundDrotrecogin 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.ObjectiveTo compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing < or =135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients.MethodsPROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups.ResultsPatient weight range was 59-227 kg. There were 32 patients < or =135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range [IQR] 0.37-0.54) for patients < or =135 kg and 0.42 L/h/kg (IQR 0.33-0.54) for patients >135 kg (p = 0.692). Median estimates of Css 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 < or =135 kg, DrotAA had a median t1/2 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 t1/2 of 16.3 minutes (IQR 14.2-18.8).ConclusionsThere is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing < or =135 kg and >135 kg. DrotAA should be dosed by actual body weight.

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