1556P - Evaluation of exposure of regorafenib and its metabolites in cancer patients with renal impairment by modelling, simulation, and clinical study

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Anticancer Agents
Cancer in Special Situations
Biological Therapy
Presenter MIchael Block
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors M. Block1, B. Ploeger2, J. Grevel3, K. Schnizler4, M. Gerisch5, F. Hafner5, S. Reschke6, F. Huang7, Z.J. Trnkova6, I. Sturm6, A. Cleton6
  • 1Systems Pharmacology Oncology, Bayer Technology Services GmbH, 51368 - Leverkusen/DE
  • 2Clinical Pharmacometrics, Bayer Pharma AG, Berlin/DE
  • 3Clinical Pharmacokinetics, BAST Inc. Limited, Loughborough/GB
  • 4Systems Pharmacology Oncology, Bayer Technology Services GmbH, Leverkusen/DE
  • 5Drug Metabolism And Pharmacokinetics, Bayer Pharma AG, Wuppertal/DE
  • 6Clinical Pharmacology Oncology, Bayer Pharma AG, Berlin/DE
  • 7Clinical Pharmacology Oncology, Bayer HealthCare Pharmaceuticals, Whippany/US



Regorafenib (Stivarga®) is an oral multikinase inhibitor which targets angiogenic, stromal, and oncogenic receptor tyrosine kinases and is currently approved in metastatic colorectal cancer and advanced gastrointestinal stromal tumors. Regorafenib is predominantly metabolized in the liver by cytochrome P450 (CYP) 3A4 and uridinediphosphate-glucuronosyltransferase (UGT) 1A9. As cancer patients treated with regorafenib may have varying degrees of renal impairment, physiology-based pharmacokinetic (PBPK) modeling and simulation was used to further estimate the effect of renal impairment on the pharmacokinetics (PK) of regorafenib and its two pharmacologically active metabolites M-2 and M-5. A phase 1 study (NCT01853046) with regorafenib in cancer patients with severe renal impairment and a control group with normal renal function or mild renal impairment was subsequently designed based on the PBPK simulations.


A PBPK model using in vitro and clinical data was used to characterize the PK of regorafenib. In addition, published data on normal renal function versus pathophysiological changes typical for patients with renal impairment were integrated, including changes in CYP 3A4 activity. The impact of end-stage renal disease (ESRD; GFR level


Based on the PBPK simulations, the PK of regorafenib, M-2, and M-5 are unlikely to be impaired by any stage of renal impairment. The PBPK predicted mean regorafenib AUC(0–24) after multiple dosing in patients with normal renal function was 69.7 mg·h/L compared with 80.8 mg·h/L in patients with ESRD. Therefore, the approved dose of regorafenib (160 mg qd in a 3 week on/1 week off schedule) was deemed safe as a starting dose for the phase 1 study.


Integrating in vitro and clinical data as well as the effects of end stage renal disease on the physiological functions in a PBPK approach estimated that the PK of regorafenib is unlikely to be impacted by any stage of renal impairment.

Clinical trial identification

Legal entity responsible for the study





M. Block, B. Ploeger, K. Schnizler, F-T. Hafner, S. Reschke, F. Huang, Z.J. Trnkova: Other substantive relationships: Bayer (employee). J. Grevel: Stock ownership: BAST. M. Gerisch: Stock ownership: Bayer Other substantive relationships: Bayer (employee). I. Sturm: Stock ownership: Bayer. Other substantive relationships: Bayer (employee). A. Cleton: Stock ownership: Bayer, AstraZeneca, Pfizer. Other substantive relationships: Bayer (employee).