The impact of concomitant ivosidenib on triazole levels in patients with AML or MDS

The IDH1 inhibitor ivosidenib, used in the treatment of acute myeloid leukemia (AML), induces several cytochrome isoenzymes and is both a substrate and inhibitor of several transporter proteins. Patients diagnosed with AML are at an increased risk of invasive fungal infections and so are regularly recommended posaconazole and voriconazole therapy. These triazole therapies are also known to cause cytochrome enzyme inhibition and the use of these agents in combination with ivosidenib may result in a lower therapeutic efficacy.

Recently, Dinh et al.¹ reported on the incidence of subtherapeutic triazole levels in patients with AML or myelodysplastic syndromes treated with concomitant ivosidenib in Cancer. We summarize the findings below.

Methods¹

• This retrospective, single-center, cohort study included patients treated between March 4, 2016, and April 30, 2022.
• Subtherapeutic triazole levels were defined as posaconazole <700 ng/ml and voriconazole <1.0 μg/ml.
• Undetectable triazole levels were defined as posaconazole <50 ng/ml and voriconazole <0.1 μg/ml.

Key findings¹

• N = 31
• All patients except one received 500 mg of ivosidenib once daily
  • One patient initially received 250 mg once daily, but this dose was later increased to 500 mg once daily
• The median triazole levels were significantly lower in patients receiving concomitant vs non-concomitant ivosidenib (p < 0.05).
• Concomitant ivosidenib was associated with a higher frequency of subtherapeutic triazole levels vs non-concomitant ivosidenib (Figure 1).

^*Adapted from Dinh, et al.^1
†Total posaconazole levels were measured in 43 patients treated with concomitant ivosidenib; total posaconazole levels were measured in 19 patients who did not receive concomitant ivosidenib.
^‡Total voriconazole levels were measured in 36 patients treated with concomitant ivosidenib; total voriconazole levels were measured in six patients who did not receive concomitant ivosidenib.

 

• During ivosidenib therapy, posaconazole was undetectable in 5% of patients, and voriconazole in 31%.
• 16% of patients experienced a new invasive fungal infection during ivosidenib treatment
  • 83% of these cases were in patients also receiving posaconazole
  • 17% of these cases were also during receiving voriconazole
  • All these patients had subtherapeutic triazole levels
• Overall, 16% of patients experienced Grade ≥3 QTc interval prolongation.

Key learnings

Levels of voriconazole were frequently subtherapeutic or undetectable in patients receiving concomitant ivosidenib, indicating it to be a potentially unreliable fungal prophylactic and treatment option. Posaconazole levels were also often subtherapeutic, suggesting the need for high empiric dosing if used as a treatment option. Therapeutic drug monitoring should be recommended to all patients treated with a triazole and concomitant ivosidenib. Further pharmacokinetic investigations of any combination therapies involving ivosidenib are warranted due to its induction effects on CYP450 isoenzymes.