Pharmacokinetic Drug Interactions of Gefitinib with Rifampicin, Itraconazole and Metoprolol

  title={Pharmacokinetic Drug Interactions of Gefitinib with Rifampicin, Itraconazole and Metoprolol},
  author={Helen C. Swaisland and Malcolm R Ranson and Robert P. Smith and Joanna Leadbetter and Alison Laight and D. Mckillop and Martin Wild},
  journal={Clinical Pharmacokinetics},
AbstractBackground 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… 

Exploring the Relationship Between Expression of Cytochrome P450 Enzymes and Gefitinib Pharmacokinetics

Although higher exposure to gefitinib occurs in individuals who are poor CYP2D6 metabolisers, genotyping prior to initiation of therapy and dosage adjustment are not warranted and no apparent relationship was observed between the occurrence of the CYP3A5 expresser genotype and gef itinib plasma clearance or terminal elimination halflife.

Pharmacokinetic Drug Interactions of Apatinib With Rifampin and Itraconazole

In vitro data indicate that cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of apatinib, whereas a strong CYP3A inhibitor (itraconazole 100 mg once a day) had a weak effect and whether these effects are of clinical significance needs further research.

The effect of rifampin on the pharmacokinetics of famitinib in healthy subjects.

Co-administration of rifampin considerably reduces plasma concentration of famitinb due to CYP3A4 induction, whereas when simultaneous use with inducers of CYP 3A4, dose adjustment of fam itinb is recommended.

CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors.

As an in vivo phenotypic probe of CYP3A, midazolam oral clearance may have utility for prediction of gefitinib exposure and dose selection and has potential for optimization of treatment with gef itinib and other TK inhibitors that are metabolized in a similar manner.

Effect of Rifampicin on the Pharmacokinetics of Lenvatinib in Healthy Adults

Lenvatinib exposure was increased by P-gp inhibition; however, based on free concentrations, simultaneous P- gp and CYP3A4 induction results met the prespecified bioequivalence 90 % confidence interval.

Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors

Investigation is required to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess the clinical relevance of interaction potential and inhibitory effects on the metabolizing enzymes and transporters.

Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole

Exposure to vandetanib, as assessed by AUC504 in healthy subjects, was reduced by around 40% when a single dose was given in combination with the potent CYP3A4 inducer rifampicin.

Differential Metabolism of Gefitinib and Erlotinib by Human Cytochrome P450 Enzymes

The differential metabolizing enzyme profiles suggest that there may be differences in drug-drug interaction potential and that stimulation of CYP3A4 may likely play a role in drug interactions for erlotinib and gefitinib.

Gefitinib-phenytoin interaction is not correlated with the C-erythromycin breath test in healthy male volunteers.

The significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass.

Metabolism-related pharmacokinetic drug−drug interactions with tyrosine kinase inhibitors: current understanding, challenges and recommendations

The objective of this review is to highlight the current understanding of DDIs among TKIs, with a focus on metabolism, as well as to identify challenges in the prediction ofDDIs and provide recommendations.



Effects of the Antifungal Agents on Oxidative Drug Metabolism

The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections.

Pharmacokinetic evaluation of gefitinib when administered with chemotherapy.

  • L. Hammond
  • Biology, Medicine
    Clinical lung cancer
  • 2003
In phase I clinical trials, gefitinib was found to be well tolerated, with clinical efficacy observed well below the maximum tolerated dose, and there was no apparent increase in higher-grade toxicity.

Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment.

The pronounced effect of the CYP2D6 genotype persists during long-term therapy, affecting both metabolic ratio and metoprolol plasma concentration.

Use of In Vitro and In Vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic Interactions

A database containing information about the clearance routes for over 300 drugs from multiple therapeutic classes, including analgesics, anti-infectives, psychotropics, anticonvulsants, cancer chemotherapeutics, gastrointestinal agents, cardiovascular agents and others, was constructed to assist in the semiquantitative prediction of the magnitude of potential interactions with drugs under development.

Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines

A novel class of EGF-RTK inhibitors are defined which are also potent and selective inhibitors of E GF-stimulated human tumour cell growthin vitro.

The area under the plasma concentration–time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin

Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great change in the AUC of oral midazolam, which is greatly decreased by itraconazole and increased by rifampicin.

Effects of propofol on human hepatic microsomal cytochrome P450 activities.

In vitro-in vivo extrapolation indicates that the degree of inhibition of CYP1A2, 2C9 and 3A4 activity which could theoretically be produced in vivo by propofol is relatively low (40-51%); this is considered unlikely to have any pronounced clinical significance.

Effect of itraconazole on the pharmacokinetics of atorvastatin

Itraconazole. A reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections.

Itraconazole along with other established agents should be considered a first-line treatment for patients with extensive or recalcitrant cutaneous fungal infections, mixed dermatophyte and Candida onychomycosis or vaginal candidiasis.