Nonclinical pharmacokinetics and activity of etirinotecan pegol (NKTR-102), a long-acting topoisomerase 1 inhibitor, in multiple cancer models

Cancer Chemother Pharmacol. 2014 Dec;74(6):1125-37. doi: 10.1007/s00280-014-2577-7. Epub 2014 Sep 17.


Purpose: The aim of the study was to demonstrate the activity of etirinotecan pegol, a polymer conjugate of irinotecan, in multiple human tumor models and to establish both the pharmacokinetic/pharmacodynamics (PK/PD) relationship and clinical relevance of the findings.

Experimental design: Anti-tumor activity was evaluated in mouse models of human lung, colorectal, breast, ovarian, and gastric cancers. Etirinotecan pegol was administered intravenously (once or every 3-7 days) to animals with established tumors. Activity was assessed by tumor growth delay (TGD) and regression. Mice bearing established colorectal and lung tumors were treated with etirinotecan pegol or irinotecan, and serial blood and tumor samples were collected at planned times between 0 and 60 days post-treatment for quantitation of etirinotecan pegol and SN38. For PK analysis, analyte concentration-time data were fit with compartmental models; PK/PD analysis was based on an inhibitory E max response model.

Results: Etirinotecan pegol was active in all tumor models. TGD was sustained for 2-10 weeks after last dose, while conventional irinotecan resulted in little suppression of tumor growth. Etirinotecan pegol was eliminated very slowly from the tumor (t 1/2 = 17 days), achieving higher and more sustained tumor exposure when compared with conventional irinotecan. The increased tumor exposure following etirinotecan pegol correlated with strong and prolonged suppression of tumor growth. Sustained plasma exposure to active SN38 was consistently observed across nonclinical species (including mouse, rat, and dog) and translated to cancer patients.

Conclusions: Etirinotecan pegol is the first long-acting topoisomerase 1 inhibitor that provides sustained exposure, which results in prolonged anti-tumor activity in a wide variety of cancer models.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Dogs
  • Female
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage*
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Irinotecan
  • Male
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Polyethylene Glycols / administration & dosage*
  • Polyethylene Glycols / pharmacokinetics
  • Polyethylene Glycols / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity
  • Topoisomerase I Inhibitors / administration & dosage*
  • Topoisomerase I Inhibitors / pharmacokinetics
  • Topoisomerase I Inhibitors / pharmacology
  • Treatment Outcome
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Heterocyclic Compounds, 4 or More Rings
  • Topoisomerase I Inhibitors
  • Polyethylene Glycols
  • Irinotecan
  • etirinotecan pegol
  • Camptothecin