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PHARMACOKINETICS

Obesity Does Not Alter the Pharmacokinetics of Drotrecogin Alfa (Activated) in Severe Sepsis

Medical Director, Acute Care, US Medical Division, Eli Lilly and Company, Indianapolis, IN

David Small, PhD

Principal Research Scientist, Global PK/PD/TS Registration Phase, Eli Lilly and Company

Darell E Heiselman, DO

Chief, Critical Care Medicine, Akron General Medical Center, Akron, OH

Richard Riker, MD

Department of Critical Care Medicine, Maine Medical Center, Portland, ME

Jay Steingrub, MD

Assistant Professor of Medicine, Critical Care Division, Baystate Medical Center, Springfield, MA

Ruqin Chen, MS

Statistical Analyst, Commercial Info Sciences, Eli Lilly and Company

Rebecca L Qualy, MS

Senior Scientific Communication Associate, Scientific Communications, Eli Lilly and Company

Christelle Darstein, MS

Statistician, Program Phase Cardiovascular/Oncology, Eli Lilly and Company

Ellen Mongan, MD

Senior Therapeutic Associate, Clinical Plans-Critical Care-Xigris, Eli Lilly and Company

Reprints: Dr. Levy, Eli Lilly and Company, Lilly Corporate Center, Drop Code 6835, Indianapolis, IN, 46285, fax 317/277-8195, hlevy{at}lilly.com

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 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 (Cl_p) 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 135 kg and 20 patients >135 kg enrolled. Median Cl_p was 0.45 L/h/kg (interquartile range [IQR] 0.37-0.54) for patients 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 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 135 kg and >135 kg. DrotAA should be dosed by actual body weight.

Key Words: drotrecogin alfa (activated), half-life, human research, obesity, pharmacokinetics, recombinant human activated protein C, severe sepsis

Published Online, January 4, 2005. www.theannals.com, DOI 10.1345/aph.1E386