Drotrecogin alfa (also known as drotrecogin alfa (activated) or recombinant human activated protein C) is a recombinant form of the naturally occurring protein C enzyme, engineered to be in its activated state. It functions as an anticoagulant and possesses anti‑inflammatory and cytoprotective properties.
Chemical and pharmacological characteristics
- Structure: Drotrecogin alfa is a 419‑amino‑acid, single‑chain glycoprotein with a molecular weight of approximately 46 kDa. It is produced in Chinese hamster ovary (CHO) cells through recombinant DNA technology, yielding a protein that is biologically identical to human activated protein C (APC) except for its glycosylation pattern.
- Mechanism of action: Activated protein C inactivates coagulation factors Va and VIIIa, thereby reducing thrombin generation. In addition, it exerts endothelial protective effects via protease‑activated receptor‑1 (PAR‑1) signaling, modulating inflammatory cascades and reducing apoptosis.
Clinical development and therapeutic use
Drotrecogin alfa was developed as a treatment for severe sepsis with high risk of mortality. In 2001, the U.S. Food and Drug Administration (FDA) granted accelerated approval for the drug (marketed under the brand name Xigris) for adult patients with severe sepsis and a documented high risk of death, as defined by an APACHE II score ≥25 or the presence of multiple organ dysfunction. The approval was based on the results of the PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) randomized controlled trial, which demonstrated a reduction in 28‑day all‑cause mortality compared with placebo (relative risk reduction ≈ 20%).
Regulatory status and withdrawal
Subsequent studies, including the PROWESS‑S trial (published in 2012), failed to confirm a mortality benefit and identified an increased risk of serious bleeding. In October 2011, Eli Lilly and Company voluntarily withdrew drotrecogin alfa from the United States and European markets, and the FDA formally removed its marketing authorization. The drug is no longer commercially available.
Safety profile
The most common adverse events were bleeding complications, particularly intracranial hemorrhage. Contraindications included active bleeding, recent major surgery, stroke, or a known high risk of hemorrhage.
Pharmacokinetics
- Administration: Intravenous infusion, typically 24 µg·kg⁻¹·h⁻¹ over a 96‑hour period.
- Distribution: Exhibits rapid plasma distribution with a volume of distribution approximating total body water.
- Metabolism and elimination: Cleared primarily by proteolytic degradation; the terminal half‑life is about 8 hours.
Research and legacy
While drotrecogin alfa itself is no longer in clinical use, its development contributed to the broader understanding of the protein C pathway in sepsis pathophysiology and informed subsequent investigational agents targeting coagulation and inflammation. The experience also highlighted challenges in translating surrogate biomarker improvements into definitive survival benefits.