CYP3A4*22 genotype-guided dosing of TKIs in cancer patients: a new way of personalized therapy

Since a few decades, tyrosine kinase inhibitors (TKI) are widely used for the treatment of cancer. These type of drugs are predominantly metabolized by CYP3A4. CYP3A4 activity is highly variable among patients since it could vary 10-100 times between individuals. Since the expression of CYP3A4 mRNA is significantly correlated with the protein expression of CYP3A4, CYP3A4*22 will also lead to a lower level of CYP3A4 protein.
For this reason CYP3A4*22 variant carriers have less functional CYP3A4 enzyme which results in higher systemic exposure and less clearance of drugs. Recent publications demonstrated that the clearance of pazopanib and sunitinib is lowered because of the CYP3A4*22 variant. Therefore our hypothesis is that the exposure of CYP3A4*22 carriers is not lowered when patients are dosed with 66%-80% of the registered dose compared to the control group.

In short, in previous studies is proven that CYP3A4*22 results in a lower clearance of TKIs metabolised by CYP3A4*22 and even can result in a higher exposure when a drug is metabolised bij CYP3A4. A higher exposure can lead to a higher incidence of toxicities caused by the drug. Due to this quality of life could be lowered for a patient. Moreover, there is a chance that the treatment for this patient has to be stopped because of the toxicity experienced by the patient. If there is evidence that CYP3A4*22 carriers have at least the same exposure when they are treated with a dosereduction of 25-33%, a relative simple intervention could realize
a effective treatment with a lower chance of adverse events and toxicity.

The aim of the study is to show that patients with the *22-variant can be safely given a lower dose of medication (i.e. ~75%) without a decrease in exposure compared to patients without the *22-variant who receive the standard dose of medication (i.e. 100%).

Steady-state