Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 3, pp 545–558 | Cite as

An allometric pharmacokinetic/pharmacodynamics model for BI 893923, a novel IGF-1 receptor inhibitor

  • Melanie I. Titze
  • Otmar Schaaf
  • Marco H. Hofmann
  • Michael P. Sanderson
  • Stephan K. Zahn
  • Jens Quant
  • Thorsten Lehr
Original Article
  • 279 Downloads

Abstract

Purpose

BI 893923 is a novel IGF1R/INSR inhibitor with promising anti-tumor efficacy. Dose-limiting hyperglycemia has been observed for other IGF1R/INSR inhibitors in clinical trials. To counterbalance anti-tumor efficacy with the risk of hyperglycemia and to determine the therapeutic window, we aimed to develop a translational pharmacokinetic/pharmacodynamics model for BI 893923. This aimed to translate pharmacokinetics and pharmacodynamics from animals to humans by an allometrically scaled semi-mechanistic model.

Methods

Model development was based on a previously published PK/PD model for BI 893923 in mice (Titze et al., Cancer Chemother Pharmacol 77:1303–1314, 13). PK and blood glucose parameters were scaled by allometric principles using body weight as a scaling factor along with an estimation of the parameter exponents. Biomarker and tumor growth parameters were extrapolated from mouse to human using the body weight ratio as scaling factor.

Results

The allometric PK/PD model successfully described BI 893923 pharmacokinetics and blood glucose across mouse, rat, dog, minipig, and monkey. BI 893923 human exposure as well as blood glucose and tumor growth were predicted and compared for different dosing scenarios. A comprehensive risk–benefit analysis was conducted by determining the net clinical benefit for each schedule. An oral dose of 2750 mg BI 893923 divided in three evenly distributed doses was identified as the optimal human dosing regimen, predicting a tumor growth inhibition of 90.4% without associated hyperglycemia.

Conclusion

Our model supported human therapeutic dose estimation by rationalizing the optimal efficacious dosing regimen with minimal undesired effects. This modeling approach may be useful for PK/PD scaling of other IGF1R/INSR inhibitors.

Keywords

PK/PD modeling Allometric scaling IGF1R/INSR inhibitor Net clinical benefit Human therapeutic dose estimation 

Abbreviations

BW

Body weight

BrW

Brain weight

IGF

Insulin-like growth factor

INSR

Insulin receptor

IIV

Interindividual variability

NCB

Net clinical benefit

PD

Pharmacodynamics

PK

Pharmacokinetics

TGI

Tumor growth inhibition

THG

Duration of hyperglycemia

VPC

Visual predictive check

Notes

Acknowledgements

We thank the following colleagues for their excellent technical assistance: Ida Dinold, Norbert Eidkum, Stefan Fischer, Astrid Jeschko, Matthias Klemencic, Katharina Mayr, Reiner Meyer, Thomas Pecina, Christian Salamon, Michaela Streicher, and Susanne Wollner-Gaida.

Compliance with ethical standards

Conflict of interest

Thorsten Lehr has received research grants from Boehringer Ingelheim and is a consultant member of Boehringer Ingelheim. Otmar Schaaf, Marco H. Hofmann, Michael P. Sanderson, Stephan K. Zahn, and Jens Quant are employees of Boehringer Ingelheim.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

280_2017_3252_MOESM1_ESM.pdf (2.1 mb)
Supplementary material 1 (PDF 2156 KB)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Melanie I. Titze
    • 1
  • Otmar Schaaf
    • 2
  • Marco H. Hofmann
    • 2
  • Michael P. Sanderson
    • 2
  • Stephan K. Zahn
    • 2
  • Jens Quant
    • 2
  • Thorsten Lehr
    • 1
  1. 1.Clinical PharmacySaarland UniversitySaarbrückenGermany
  2. 2.Boehringer Ingelheim RCV GmbH & Co KGViennaAustria

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