Liver Necrosis in a Patient Receiving Isavuconazole: Making the Case for Therapeutic Drug Monitoring

Abstract

An 81-year-old man prescribed isavuconazole for pulmonary fungal infection developed high serum transaminase levels and biopsy-confirmed hepatic necrosis associated with prolonged high serum isavuconazole levels. Genotyping revealed poor CYP3A5 activity/normal CYP3A4 activity. Older age and slow isavuconazole elimination likely led to isavuconazole-associated hepatic toxicity. This case underscores the importance of isavuconazole therapeutic drug monitoring.

In the decade since its approval by the Food and Drug Administration, isavuconazole, available as the pro-drug isavuconazonium, has been shown to be well tolerated with little toxicity, fewer drug-drug interactions than most other triazoles, and largely predictable pharmacokinetics [1–5]. It has been suggested that routine therapeutic drug monitoring (TDM) is not necessary for isavuconazole because of the reported excellent safety and pharmacokinetic profiles and that TDM might be needed only if a patient has not responded to therapy as expected, has issues that might cause variability in pharmacokinetics, or is being treated for a fungal pathogen with a high minimum inhibitory concentration for isavuconazole [3, 6, 7].

CASE REPORT

An 81-year-old man experienced pleuritic chest pain and dyspnea while vacationing in Florida in February 2024. A thoracic computed tomographic (CT) scan revealed multifocal pneumonia and a right middle lobe cavitary lesion; honeycomb changes and traction bronchiectasis were also noted. Fungal organisms were seen on tissue obtained by bronchoscopic biopsy, but no fungi were isolated in culture. The patient was told that he had a black mold infection and was treated with isavuconazole (200 mg [isavuconazonium sulfate, 372 mg] daily); no serum isavuconazole concentrations were obtained. His pulmonary symptoms resolved over the next month, but isavuconazole therapy was continued until he returned to Michigan in May 2024.

The patient was seen in the Infectious Diseases Clinic at the University of Michigan on May 20, 2024 with concerns about whether he needed to continue antifungal therapy. At that time, he denied symptoms. His medical history revealed hypertension, benign prostatic hypertrophy, and a prior pulmonary embolism. Medications included isavuconazole, lisinopril, apixaban, finasteride, and alfuzosin. The patient had no history of liver disease and reported no use of dietary supplements before or after initiation of isavuconazole therapy. He reported adherence to the prescribed isavuconazole dose. On examination, he was a healthy-appearing older man with a temperature of 97.5^°F, blood pressure of 128/60 mm Hg, pulse rate of 59 beats/min, and respiration rate of 16/min. His chest was clear to auscultation, no murmurs were heard, his abdomen was nontender, and he had no hepatomegaly.

Laboratory studies revealed a white blood cell count 4900/µL, a hemoglobin level of 15 g/dL, and a creatinine level of 0.78 mg/dL. The patient’s serum transaminase enzyme levels were elevated (alanine aminotransferase [ALT], 674 U/L; aspartate aminotransferase [AST]. 318 U/L), while his alkaline phosphatase (80 U/L), bilirubin (0.7 mg/dL), and albumin (4.2 g/dL) were within normal limits. His serum isavuconazole concentration was >10 µg/mL as measured using liquid chromatography–tandem mass spectrometry (Eurofins Viracor). Isavuconazole was stopped immediately, but the serum concentration remained >5 µg/mL for >3 weeks and was still measurable 3 months after the drug was stopped (Figure 1).

Figure 1.

Trends in transaminase and serum isavuconazole concentrations in a patient with isavuconazole-associated liver injury. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Because the patient’s serum transaminase levels were increasing and his bilirubin began to rise, a gastroenterology consultation was requested, and a liver biopsy was performed on June 17, 2024, revealing active hepatitis with centrizonal necrosis and hepatocyte dropout, favoring drug-induced liver injury (Figure 2). Prednisone therapy was initiated at a dose of 30 mg twice daily for 2 weeks and was slowly tapered until discontinuation on July 31, 2024. The patient’s AST and ALT fell to normal levels by July 22, 2024. Throughout this time, he had no symptoms suggesting hepatic disease.

Figure 2.

Liver biopsy showing centrizonal necrosis and hepatocyte dropout (arrow) thought to be related to isavuconazole-associated toxicity.

To possibly explain the persistently high isavuconazole serum concentrations, cytochrome P450 genotype studies were performed (ARUP Laboratories). Testing showed that CYP3A4 genotype alleles were *1/*1 (normal metabolizer phenotype) but that CYP3A5 genotype alleles were *3/*3 (poor metabolizer phenotype). Follow-up thoracic CT examinations showed slow resolution of the pulmonary cavity in the right middle lobe and persistence of interlobular septal thickening and traction bronchiectasis.

DISCUSSION

Isavuconazole is increasingly used in the management of invasive aspergillosis, mucormycosis, and other severe fungal infections [8–10]. Its appeal lies in a favorable safety profile, once-daily dosing, and fewer clinically relevant drug-drug interactions than with other triazoles. An exposure-response analysis from the SECURE trial did not identify any statistically significant associations between isavuconazole exposure and efficacy or safety [9, 11]. Based partly on this analysis, routine TDM was deemed not necessary and therefore not routinely recommended.

Postmarketing clinical experience, however, suggests that isavuconazole serum concentrations may vary among different patient populations. For example, critically ill patients and obese patients have been noted to have lower-than-expected isavuconazole levels [12–14]. Other studies have noted that isavuconazole serum concentrations increase over time in patients on prolonged therapy and also have shown that greater isavuconazole exposure is associated with increased risk of toxicity [6, 15, 16].

The association of elevated serum isavuconazole concentrations with possible hepatic toxicity has been noted in only a few reports. A study of 45 patients taking isavuconazole for chronic pulmonary aspergillosis reported hepatic toxicity leading to drug discontinuation in 4 patients, 1 of whom had grade 2 toxicity; isavuconazole serum concentrations in these 4 patients ranged from 2.85 to 7.48 µg/mL [17]. In a patient who had received a hematopoietic cell transplant, had hepatic graft-versus-host disease, and who had taken isavuconazole for 3 months, liver biopsy, performed when AST and ALT reached levels >1000 U/L, revealed histology similar to but more severe than that described in our patient; unfortunately, no isavuconazole serum levels were obtained [18]. In a retrospective evaluation of 95 patients receiving isavuconazole, it was determined that serum concentrations >5.86 µg/mL were associated with increased risk of toxicity; transaminitis, occurring in 30% of patients, was the most common adverse event noted in this cohort [16]. In all of the above reports, dose reduction of isavuconazole led to resolution of toxicity.

Emerging evidence suggests that pharmacogenomics may have an important role in azole antifungal therapy by providing critical insights into the influence of cytochrome P450 (CYP450) enzyme polymorphisms on drug pharmacokinetics, efficacy, and toxicity. Genetic variability in CYP450 isoforms, particularly CYP2C19, CYP2C9, and CYP3A4, can result in substantial interindividual differences in azole metabolism, thereby affecting systemic drug concentrations, drug-drug interactions, and clinical response [19]. None of the patient's concomitant medications, 3 of which are metabolized by CYP3A4, have been found to increase isavuconazole serum concentrations or cause liver toxicity.

Genomics testing in patients receiving azole therapy has the potential to inform individualized antifungal treatment strategies, enabling clinicians to anticipate altered drug exposure, reduce the occurrence of adverse effects, optimize therapeutic efficacy and improve patient outcomes. Isavuconazole is metabolized primarily via hepatic CYP3A4 and to a lesser extent via CYP3A5 [20]. Our patient had the CYP3A5*3/*3 polymorphism, identifying a lack of CYP3A5 activity, but he had a normal CYP3A4 metabolizer phenotype, the isoenzyme primarily responsible for isavuconazole metabolism. It seems unlikely that this polymorphism, by itself, explains the prolonged high serum isavuconazole concentrations that we found.

Several studies suggest that elderly patients are at higher risk of toxicities when treated with isavuconazole [16, 17, 21, 22]. A post hoc analysis of the safety and efficacy of isavuconazole from the VITAL and SECURE studies found that patients >65 years of age experienced higher rates of serious adverse events than younger patients, including liver toxicity [21]. In our patient, the serum isavuconazole concentration exceeded 10 µg/mL for a prolonged period and was associated with elevation of transaminases and biopsy-confirmed drug-induced hepatitis. It is possible that both older age and the CYP3A5*3/*3 polymorphism contributed to the prolonged high serum concentrations and the toxicity of isavuconazole.

In conclusion, routine TDM is not recommended for every patient receiving isavuconazole, but our case demonstrates that some patients are at risk for drug accumulation and possible hepatic injury. This appears to be more likely in older adults and in patients who are treated with isavuconazole for several months. We suggest that obtaining isavuconazole serum levels and transaminase values are important components of the follow up of patients, especially those who are older and who are treated with isavuconazole for more than a few weeks. The role of pharmacogenetic testing in clinical practice is less understood but may be useful in determining the reasons for unexpectedly high serum isavuconazole levels.