Management of dose variability and side effects for individualized cancer pharmacotherapy with tyrosine kinase inhibitors

Pharmacol Ther. 2015 Aug;152:125-34. doi: 10.1016/j.pharmthera.2015.05.009. Epub 2015 May 11.

Abstract

Molecular-targeted therapies with tyrosine kinase inhibitors (TKIs) have provided a major breakthrough in cancer treatment. These agents are given orally and demonstrated to be substrates for drug transporters. In clinical settings, TKIs are mainly used at a fixed dose, but wide interpatient variability has been observed in their pharmacokinetics and/or pharmacodynamics. Genetic polymorphisms of ABC transporters, drug-drug interaction and adherence are among the factors causing such variation. To overcome these problems, therapeutic drug monitoring has been applied in clinical practice for patient care. Skin disorders are frequently observed as adverse drug reactions when using TKIs, and are commonly managed by symptomatic therapy based on clinical experience. Recent studies have provided some insights into the molecular mechanisms underlying skin disorders induced by TKIs. This review article summarizes the accumulated clinical and basic pharmacological evidence of TKIs, focusing on erlotinib, sorafenib and sunitinib.

Keywords: Drug interaction; Drug transporter; Skin disorders; Therapeutic drug monitoring; Tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Disease Management
  • Dose-Response Relationship, Drug
  • Drug Monitoring / methods
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology*
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases