Higher Systemic Exposure to Unbound Active Metabolites of Regorafenib Is Associated With Short Progression-Free Survival in Colorectal Cancer Patients

Clin Pharmacol Ther. 2020 Sep;108(3):586-595. doi: 10.1002/cpt.1810. Epub 2020 Mar 10.

Abstract

Regorafenib treatment improves survival of patients with metastatic colorectal cancer, but it is also characterized by detrimental side effects that may require modified dosing or interval schedules. Regorafenib is metabolized by cytochrome P450 3A4 in the liver to its active metabolites, M-2 and M-5. We examined area under the unbound plasma concentration-time curve (AUCu) to these compounds to establish pharmacokinetic bases for individualized dosing strategies. The plasma protein binding of M-2 and M-5 was approximately 10-fold lower than that of regorafenib, whereas AUCu values for active metabolites on both days 1 and 15 were significantly higher than that of regorafenib. Patients with higher AUCu values of M-2 or M-5 on day 1 showed significantly shorter progression-free survival than others, likely due, at least in part, to treatment discontinuation as a result of adverse events, especially occurred during first cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Activation, Metabolic
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Colorectal Neoplasms / blood
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Dosage Calculations
  • Female
  • Humans
  • Liver / enzymology
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Pharmacogenomic Variants
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / adverse effects
  • Phenylurea Compounds / blood
  • Phenylurea Compounds / pharmacokinetics*
  • Polymorphism, Genetic
  • Progression-Free Survival
  • Prospective Studies
  • Protein Binding
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Pyridines / blood
  • Pyridines / pharmacokinetics*

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Phenylurea Compounds
  • Pyridines
  • regorafenib
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human