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Isavuconazole: Case Report and Pharmacokinetic Considerations
Francesco Marchesi1, Corrado Girmenia2, Bianca Maria Goffredo3
1Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Abstract:
Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a "probable" IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity; however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti-infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM.
Insights
Isavuconazole (IVZ) demonstrated stable plasma concentrations and no drug interactions during chemotherapy for acute lymphoblastic leukemia (ALL). This suggests that therapeutic drug monitoring for IVZ may not be necessary in clinical practice.
Area of Science:
- Mycology
- Pharmacology
- Hematology
Background:
- Invasive fungal disease (IFD) poses significant risks for immunocompromised patients.
- Voriconazole (VCZ) and posaconazole (PCZ) are common antifungals but have drug-drug interactions and pharmacokinetic variability.
- Isavuconazole (IVZ) is a newer antifungal with promising pharmacokinetic properties, but real-world data on its use and therapeutic drug monitoring (TDM) is limited.
Observation:
- A patient with acute lymphoblastic leukemia (ALL) developed probable invasive aspergillosis (IA) during chemotherapy.
- Initial treatment with VCZ led to severe hepatic toxicity due to high plasma levels.
- Switching to IVZ resulted in stable drug concentrations despite concurrent chemotherapy, but hepatic toxicity recurred.
- Hepatic toxicity resolved upon chemotherapy cessation, independent of IVZ levels, suggesting it was not directly related to IVZ plasma concentration.
Findings:
- Isavuconazole (IVZ) plasma concentrations remained stable throughout treatment in an ALL patient receiving concomitant chemotherapy.
- IVZ pharmacokinetics were unaffected by concurrent administration of multiple other medications.
- Hepatic toxicity observed during IVZ treatment was not correlated with IVZ plasma concentrations.
Implications:
- Isavuconazole (IVZ) may offer a safer alternative to older azoles in immunocompromised patients undergoing complex therapies.
- The findings suggest that TDM for IVZ might not be routinely required in clinical settings, simplifying treatment protocols.
- Further real-world studies are warranted to confirm the safety and efficacy of IVZ and its TDM requirements across diverse patient populations.
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