Ivonib (Ivitinib) Significantly Reduces Triazole Levels in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Ivonib (ivitinib) is primarily metabolized byCYP3A4; however, it induces CYP450 isoenzymes, includingCYP3A4 and CYP2C9, which inhibit drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk for invasive fungal infections, so posaconazole and voriconazole are often used in this population. Voriconazole is a substrate for CYP2C9, CYP2C19, and CYP3A4; therefore, coadministration of ivonib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily by UDP glucuronidation; therefore, the effect of ivonib on posaconazole exposure is unknown.

Includes patients receiving ivitinib and concomitant triazole therapy with at least one serum trough. Subtherapeutic levels were defined as posaconazole< 700 ng/mL and voriconazole < 1.0 g/mL. The incidence of breakthrough invasive fungal infection and QTc prolongation was determined after coadministration of ivitinib with a triazole for at least 5 days.

Serum triazole levels were assessed in317878 patients who received ivertinib-containing therapy and concomitant triazole therapy. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (Posaconazole:n= 20 [47%] of 43; voriconazole: n = 27 [77%] of 35). Median triazole serum levels were significantly lower during co-administration of ivitinib compared with levels while patients were off ivitinib. Daily500 mgThe incidence of grade QTc prolongation was not significantly increased when azole antifungals were coadministered with ivitinib.

This study showed that coadministration of ivonib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (> 300 mg/day) may be considered, and therapeutic drug monitoring is recommended for all patients concurrently receiving ivitinib.