Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model

Br J Clin Pharmacol. 2014 May;77(5):796-807. doi: 10.1111/bcp.12256.


Aims: To identify prospectively a safe therapeutic window for administration of a novel oral transforming growth factor β (TGF-β) inhibitor, LY2157299 monohydrate, based on a pharmacokinetic/pharmacodynamic (PK/PD) model. Simulations of population plasma exposures and biomarker responses in tumour were performed for future trials of LY2157299 in glioblastoma and other cancer populations.

Methods: The model was updated after completion of each cohort during the first-in-human dose (FHD) study. The flexible design allowed continuous assessment of PK variability by recruiting the required number of patients in each cohort. Based on 30% inhibition of TGF-β RI kinase phosphorylates (pSMAD), biologically effective exposures were anticipated to be reached from 160 mg onwards. The therapeutic window was predicted, based on animal data, to be between 160 and 360 mg.

Results: No medically significant safety issues were observed and no dose limiting toxicities were established in this study. Observed plasma exposures (medians 2.43 to 3.7 mg l⁻¹ h, respectively) with doses of 160 mg to 300 mg were within the predicted therapeutic window. Responses, based on the MacDonald criteria, were observed in these patients.

Conclusions: A therapeutic window for the clinical investigation of LY2157299 in cancer patients was defined using a targeted PK/PD approach, which integrated translational biomarkers and preclinical toxicity. The study supports using a therapeutic window based on a PK/PD model in early oncology development.

MeSH terms

  • Adult
  • Aged
  • Biomarkers
  • Cohort Studies
  • Drug Discovery
  • Female
  • Glioblastoma / drug therapy
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Pyrazoles / pharmacokinetics*
  • Pyrazoles / pharmacology
  • Quinolines / pharmacokinetics*
  • Quinolines / pharmacology
  • Transforming Growth Factor beta / antagonists & inhibitors*


  • Biomarkers
  • Pyrazoles
  • Quinolines
  • Transforming Growth Factor beta
  • LY-2157299