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Assessment of OATP transporter-mediated drug-drug interaction using physiologically-based pharmacokinetic (PBPK)

Yuan Chen1, Rui Zhu2, Fang Ma1

  • 1Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA, 94080, USA.

Biopharmaceutics & Drug Disposition
|October 19, 2018
PubMed

Insights

A PBPK model predicted drug-drug interactions for GDC-0810, an anti-cancer drug. The model assessed interactions with pravastatin, showing low to moderate effects, aiding clinical risk assessment for new chemical entities.

Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Computational Biology and Modeling
  • Oncology Drug Development

Background:

  • GDC-0810 is an investigational oral anti-cancer drug targeting estrogen receptor-positive breast cancer.
  • GDC-0810 is a potent inhibitor of organic anion transporting polypeptides OATP1B1/1B3.
  • Assessing transporter drug-drug interactions (tDDI) is crucial for clinical risk evaluation of new drugs.

Purpose of the Study:

  • To develop and validate a physiologically based pharmacokinetic (PBPK) model to predict tDDI between GDC-0810 and pravastatin.
  • To evaluate the clinical risk associated with GDC-0810's OATP1B1/1B3 inhibition.
  • To support the clinical development strategy for GDC-0810.

Main Methods:

  • Constructed a PBPK model in Simcyp® integrating in vitro and in vivo data for GDC-0810.
  • Verified the PBPK model using GDC-0810 Phase I clinical pharmacokinetic data.
  • Validated the Simcyp transporter DDI model with known OATP1B1/1B3 inhibitors (rifampicin, cyclosporine, gemfibrozil) and substrate (pravastatin).

Main Results:

  • The PBPK model accurately described GDC-0810's pharmacokinetic profile.
  • The model reasonably predicted pravastatin tDDI for rifampicin and gemfibrozil but under-predicted for cyclosporine.
  • Predicted GDC-0810 to have a low to moderate effect on pravastatin pharmacokinetics (Cmax ratios 1.01-2.05, AUC ratio 1.04-2.23).

Conclusions:

  • The developed PBPK model provides a reliable tool for prospectively assessing tDDI of OATP1B1/1B3 inhibitors.
  • The predicted low to moderate tDDI supports the clinical development of GDC-0810.
  • This approach aids in managing clinical risk and informing drug development strategies for new chemical entities affecting transporter proteins.
Keywords:
PBPK modeldrug-drug interactionpharmacokineticstransporter

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