Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol

Clin Pharmacokinet. 2005;44(10):1067-81. doi: 10.2165/00003088-200544100-00005.


Background and objectives: Gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, has been approved in several countries for the treatment of advanced non-small-cell lung cancer. Preclinical studies were conducted to determine the cytochrome P450 (CYP) isoenzymes involved in the metabolism of gefitinib and to evaluate the potential of gefitinib to cause drug interactions through inhibition of CYP isoenzymes. Based on these findings, three clinical studies were carried out to investigate pharmacokinetic drug interactions in vivo with gefitinib.

Methods: In preclinical studies radiolabelled gefitinib was incubated with: (i) hepatic microsomal protein in the presence of selective CYP inhibitors; and (ii) expressed CYP enzymes. Human hepatic microsomal protein was incubated with selective CYP substrates in the presence of gefitinib. Clinical studies were all phase I, open-label, single-centre studies; two had a randomised, two-way crossover design and the third was nonrandomised. The first and second studies investigated the pharmacokinetics of gefitinib in the presence of a potent CYP3A4 inducer (rifampicin [rifampin]) or inhibitor (itraconazole) in healthy male volunteers. The third study investigated the effects that gefitinib had on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in patients with solid tumours.

Results: The results of preclinical studies demonstrated that CYP3A4 is involved in the metabolism of gefitinib and that gefitinib is a weak inhibitor of CYP2D6 activity. In clinical studies when gefitinib was administered in the presence of rifampicin, geometric mean (gmean) maximum concentration and area under the plasma concentration-time curve (AUC) were reduced by 65% and 83%, respectively; these changes were statistically significant. When gefitinib was administered in the presence of itraconazole, gmean AUC increased by 78% and 61% at gefitinib doses of 250 and 500 mg, respectively; these changes also being statistically significant. Coadministration of metoprolol with gefitinib resulted in a 35% increase in the metoprolol area under plasma concentration-time curve from time zero to the time of the last quantifiable concentration; this change was not statistically significant. There was no apparent change in the safety profile of gefitinib as a result of coadministration with other agents.

Conclusions: Although CYP3A4 inducers may reduce exposure to gefitinib, further work is required to define any resultant effect on the efficacy of gefitinib. Exposure to gefitinib is increased by coadministration with CYP3A4 inhibitors, but since gefitinib is known to have a good tolerability profile, a dosage reduction is not recommended. Gefitinib is unlikely to exert a clinically relevant effect on the pharmacokinetics of drugs that are dependent on CYP2D6-mediated metabolism for their clearance, but the potential to increase plasma concentrations should be considered if gefitinib is coadministered with CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Cross-Over Studies
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Drug Combinations
  • Drug Interactions
  • Enzyme Induction
  • Enzyme Inhibitors
  • Female
  • Gefitinib
  • Humans
  • Itraconazole / administration & dosage
  • Itraconazole / pharmacokinetics
  • Itraconazole / pharmacology*
  • Male
  • Metoprolol / administration & dosage
  • Metoprolol / pharmacokinetics
  • Metoprolol / pharmacology*
  • Microsomes, Liver / enzymology
  • Middle Aged
  • Neoplasms / drug therapy
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacokinetics*
  • Quinazolines / therapeutic use
  • Rifampin / administration & dosage
  • Rifampin / pharmacokinetics
  • Rifampin / pharmacology*


  • Antineoplastic Agents
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Drug Combinations
  • Enzyme Inhibitors
  • Quinazolines
  • Itraconazole
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Metoprolol
  • Gefitinib
  • Rifampin