Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome

• Published in: Cancer Vol. 130; no. 11; pp. 1964 - 1971
• Main Authors: Dinh, Ashley, Savoy, J. Michael, Kontoyiannis, Dimitrios P., Takahashi, Koichi, Issa, Ghayas C., Kantarjian, Hagop M., DiNardo, Courtney D., Rausch, Caitlin R.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2024
• Subjects: Acute myeloid leukemia; CYP450 inducer; Drugs; drug‐drug interactions; Fungal infections; Fungi; Fungicides; Glycoproteins; Invasiveness; Isoenzymes; ivosidenib; Leukemia; Myelodysplastic syndrome; Posaconazole; Prolongation; QTc prolongation; Serum levels; Substrates; Triazoles; venetoclax; Voriconazole; posaconazole; drug-drug interactions; voriconazole; CYP450 inducer; ivosidenib; venetoclax; QTc prolongation
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.35251

Background Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P‐glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P‐glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. Methods Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. Results Seventy‐eight serum triazole levels from 31 patients receiving ivosidenib‐containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. Conclusions This study demonstrated that concomitant ivosidenib 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 in all patients receiving concomitant ivosidenib. This study explores the cytochrome P450 induction effects of ivosidenib. Patients with acute myeloid leukemia or myelodysplastic syndrome receiving ivosidenib and concomitant triazole antifungals may require additional therapeutic drug monitoring of serum azole levels or empirically higher doses to overcome the CYP450 induction effects of ivosidenib.