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 < or =135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) 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 (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.


RESULTS
Patient 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).


CONCLUSIONS
There 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.
Levy
Howard
H
Acute Care, US Medical Division, Eli Lilly and Company, Indianapolis, IN 46285, USA. hlevy@lilly.com
Small
David
D
Heiselman
Darell E
DE
Riker
Richard
R
Steingrub
Jay
J
Chen
Ruqin
R
Qualy
Rebecca L
RL
Darstein
Christelle
C
Mongan
Ellen
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D016001:Confidence Intervals; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D011486:Protein C / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood* / Q000150:complications / Q000188:drug therapy
D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated