Pharmacokinetic Drug Interactions of Apatinib With Rifampin and Itraconazole

Abstract Apatinib is a small‐molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with advanced‐stage gastric cancer or gastroesophageal junction cancer who have progressed or recurred after at least 2 kinds of systemic chemotherapy. In vitro data indicate that cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of apatinib. Pharmacokinetic drug–drug interactions of apatinib and (1) a CYP3A4 inducer (rifampin) or (2) a CYP3A inhibitor (itraconazole) were clinically evaluated in healthy volunteers. Compared with the single administration of apatinib, its coadministration with rifampin resulted in a 5.6‐fold plasma clearance (CL/F) and 83% decrease in plasma AUC 0–t of apatinib. By contrast, coadministration with itraconazole reduced the CL/F of apatinib by 40% and increased its AUC 0–t by 75%. In summary, a strong CYP3A4 inducer (rifampin) had a strong effect (>5‐fold) on the clinical pharmacokinetics of apatinib, whereas a strong CYP3A inhibitor (itraconazole 100 mg once a day) had a weak effect (1.25‐ to 2‐fold). Whether these effects are of clinical significance needs further research and information about the exposure–safety and exposure–efficacy relationship of apatinib.