1559P - Evaluation of exposure of regorafenib (REG) and its metabolites in pediatric patients by modeling, simulation, and clinical study

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Bart Ploeger
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors B. Ploeger1, J. Grevel2, M. Frede3, M. Block4, K. Schnizler4, M. Gerisch5, F. Hafner5, Z.J. Trnkova6, A.C. Agostinho7, I. Sturm6, A. Cleton6
  • 1Clinical Pharmacometrics, Bayer Pharma AG, 13353 - Berlin/DE
  • 2Clinical Pharmacometrics, BAST Inc. Limited, Loughborough/GB
  • 3Clinical Pharmacometrics, Bayer Pharma AG, Wuppertal/DE
  • 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 Development Oncology, Bayer HealthCare Pharmaceuticals, Whippany/US



REG (Stivarga®) is an oral multikinase inhibitor which is currently approved in adult patients with metastatic CRC and GIST. A phase 1 dose-finding study in pediatric patients with solid malignant tumors (EudraCT Number: 2013-003579-36) is ongoing. We used physiology-based (PBPK) and population-based PK (popPK) modeling and simulation based on knowledge about REG in adult cancer patients to simulate REG pharmacokinetics (PK) in pediatric patients, to support the clinical study design, and to evaluate the PK data of REG and its two pharmacologically active metabolites M-2 and M-5.


A PBPK model, built using data from literature and clinical studies in adult cancer patients, was used for PK simulation. Then physiological changes were integrated, including data on the growth and ontogeny of PK processes relevant for REG (e.g., cytochrome P450 3A4 activity) to scale the adult model to children. REG exposure in children (6 months to 18 years) was simulated to define dosing in the clinical study. A popPK model was developed based on the PBPK simulations to define the PK sampling time-points. During the study, exposure was estimated using the popPK model and compared with the PBPK simulations.


Using a PBPK approach, body surface area normalized dosing was found superior compared with body weight normalized dosing. The recommended starting dose for the phase 1 study was 45 and 60 mg/m2 for patients aged 6 to 24 months and 2 to 18 years, respectively. Sparse sampling with 2–5 samples per subject allowed for accurate estimation of the apparent clearance. The PBPK predictions of REG exposure were slightly higher and that of M-2 and M-5 slightly lower compared with the observed exposure in the phase 1 pediatric study. For example, in the phase 1 trial for the dose of 72 and 82 mg/m2, the geometric mean of the REG AUC(0–24) based on nominal dosing was estimated to be 43.1 and 50.1 mg*h/L, respectively.


Application of PK modeling provided an increased understanding of REG PK in pediatric patients. In addition, it allowed a sparse sampling schedule to minimize the burden for the patients in the pediatric study and supported the design of the clinical study.

Clinical trial identification

Legal entity responsible for the study





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