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Model-Based Assessments of CYP-Mediated Drug-Drug Interaction Risk of Alectinib: Physiologically Based

Yumi Cleary1, Michael Gertz1, Peter N Morcos2

  • 1Roche Innovation Center, Basel, Switzerland.

Clinical Pharmacology and Therapeutics
|December 12, 2017
PubMed

Insights

Alectinib, an ALK inhibitor for lung cancer, has low drug-drug interaction (DDI) risk. Physiologically based pharmacokinetic modeling confirmed alectinib can be safely used without dose adjustments for CYP-mediated DDIs.

Area of Science:

  • Pharmacology
  • Oncology
  • Drug Metabolism

Background:

  • Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor for ALK-positive non-small cell lung cancer.
  • In vitro studies indicated potential drug-drug interaction (DDI) risks for alectinib and its metabolite M4 involving cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8.

Purpose of the Study:

  • To investigate the clinical relevance of potential DDIs associated with alectinib.
  • To utilize physiologically based pharmacokinetic (PBPK) modeling combined with limited clinical trials to assess DDI risks.

Main Methods:

  • Physiologically based pharmacokinetic (PBPK) modeling was employed to mechanistically evaluate DDI potential.
  • A novel two-dimensional analysis of fmCYP3A4 and FG was used to assess CYP3A4-mediated victim DDI risk.
  • Limited clinical trials were conducted to gather data for PBPK model refinement and validation.

Main Results:

  • PBPK modeling indicated a low victim DDI risk for alectinib via CYP3A4.
  • Alectinib demonstrated negligible enzyme-modulating effects on CYP2C8 and CYP3A4 at clinically relevant exposures.
  • The developed PBPK model showed strong extrapolation ability for DDI risk assessment.

Conclusions:

  • Alectinib exhibits a low risk for clinically significant CYP-mediated drug-drug interactions.
  • No dose adjustments are necessary for alectinib when co-administered with drugs that affect CYP enzymes.
  • This study supports the safe and effective use of alectinib in clinical practice without concerns for CYP-mediated DDIs.

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