Midostaurin and cyclosporine drug interaction: A case report

Mancini, Robert; LaMontagne, Leslie; Williams, Travis; Kreisle, William; Petersen, Finn

doi:10.1111/jcpt.13077

Cited by 3 publications

(4 citation statements)

References 14 publications

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“…Shortly after initiating midostaurin, cyclosporin C trough increased by 70%, which was attributed to CYP3A4 inhibition by midostaurin. 17 Our case also indicates that midostaurin is not only a victim but can also act as a perpetrator of DDIs. The inhibition of CYP2C9 and CYP3A4 involved in voriconazole metabolism by midostaurin and its metabolites resulted in supratherapeutic voriconazole levels and typical related toxicity signs (visual hallucinations).…”

Section: Discussionmentioning

confidence: 56%

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Clinically relevant bidirectional drug‐drug interaction between midostaurin and voriconazole

Haefliger

Calmy

Lamoth

et al. 2023

Brit J Clinical Pharma

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Midostaurin is often prescribed with azole antifungals in patients with leukaemia, either for aspergillosis prophylaxis or treatment. Midostaurin is extensively metabolized by cytochrome (CYP) 3A4. In addition, it inhibits and induces various CYPs at therapeutic concentrations. Thus, midostaurin is associated with a high potential for drug‐drug interactions (DDIs), both as a substrate (victim) and as a perpetrator. However, data on midostaurin as a perpetrator of DDIs are scarce, as most pharmacokinetic studies have focused on midostaurin as a victim drug. We report a clinically relevant bidirectional DDI between midostaurin and voriconazole during induction treatment. A 49‐year‐old woman with acute myeloid leukaemia developed invasive pulmonary aspergillosis after induction chemotherapy. She was treated with voriconazole at standard dosage. Six days after starting midostaurin, she developed visual hallucinations with a concurrent sharp increase in voriconazole blood concentration (Ctrough 10.3 mg L−1, target Ctrough 1‐5 mg L−1). Neurotoxicity was considered to be related to voriconazole overexposure. The concentration of midostaurin was concomitantly six‐fold above the average expected level, but without safety issues. Midostaurin was stopped and the dosage of voriconazole was adjusted with therapeutic drug monitoring. The evolution was favourable, with quick resolution and no recurrence of visual hallucinations. To our knowledge, this is the first case suggesting that midostaurin and voriconazole reciprocally inhibit each other's metabolism, leading to increased exposure of both. This case highlights the knowledge gap regarding drug‐drug interactions between midostaurin and azole antifungals. Close clinical and therapeutic drug monitoring is advised in such cases.

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Section: Discussionmentioning

confidence: 56%

“…This case describes the DDI between cyclosporin (victim) and midostaurin in a 69‐year‐old patient undergoing allogeneic stem cell transplantation for FLT3‐ITD + AML. Shortly after initiating midostaurin, cyclosporin C trough increased by 70%, which was attributed to CYP3A4 inhibition by midostaurin 17 …”

Section: Discussionmentioning

confidence: 99%

Clinically relevant bidirectional drug‐drug interaction between midostaurin and voriconazole

Haefliger

Calmy

Lamoth

et al. 2023

Brit J Clinical Pharma

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“…However, in vitro studies evidenced that midostaurin does inhibit multiple cytochrome P450 isoforms (including the 3A isoform) [79]. Currently, there is little evidence available on the possible interaction between midostaurin and calcineurin inhibitors, although cases of relevant interactions have been described [80]. Therefore, careful monitoring of serum trough levels of the immunosuppressive drugs after initiation of midostaurin therapy is recommended.…”

Section: Maintenance Therapy After Allogeneic Sctmentioning

confidence: 99%

Safety of FLT3 inhibitors in patients with acute myeloid leukemia

Cerchione

Raíndo

Orgueira

et al. 2021

Expert Review of Hematology

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Introduction: Acute myeloblastic leukemia (AML) is the most frequent type of acute leukemia in adults with an incidence of 4.2 cases per 100,000 inhabitants and poor 5-year survival. Patients with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene have poor survival and higher relapse rates compared with wild-type cases. Areas covered: Several FLT3 inhibitors have been proved in FLT3 mut AML patients, with differences in their pharmacokinetics, kinase inhibitory and adverse events profiles. First-generation multi-kinase inhibitors (midostaurin, sorafenib, lestaurtinib) target multiple proteins, whereassecond-generation inhibitors (crenolanib, quizartinib, gilteritinib) are more specific and potent inhibitors of FLT3, so they are associated with less off-target toxic effects. All of these drugs have primary and acquired mechanisms of resistance, and therefore their combinations with other drugs (checkpoint inhibitors, hypomethylating agents, standard chemotherapy) and its application in different clinical settings are under study. Expert opinion:The recent clinical development of various FLT3 inhibitors for the treatment of FLT3 mut AML is an effective therapeutic strategy. However, there are unique toxicities and drug-drug interactions that need to be resolved. It is necessary to understand the mechanisms of toxicity in order to recognize and manage them adequately.

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“…Enrolled patient populations do not necessarily represent a real-world population complicating routine use upon approval [103]. Expected approval of these drugs and expanded use of midostaurin will increase clinical use and has to raise awareness in the treating medical team as potential DDI other than with antifungals while on concomitant midostaurin treatment have been identified [104]. In the specific case of midostaurin and posaconazole, it remains important to emphasize that clinicians should be reassured that posaconazole prophylaxis does neither represent a contraindication to administer midostaurin nor the other way around.…”

Section: Future Developmentsmentioning

confidence: 99%

Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma

et al. 2020

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With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug–drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITDmut-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.

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Midostaurin and cyclosporine drug interaction: A case report

Cited by 3 publications

References 14 publications

Clinically relevant bidirectional drug‐drug interaction between midostaurin and voriconazole

Clinically relevant bidirectional drug‐drug interaction between midostaurin and voriconazole

Safety of FLT3 inhibitors in patients with acute myeloid leukemia

Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma

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