Therapeutic Drug Monitoring of Isavuconazole: Serum Concentration Variability and Success Rates for Reaching Target in Comparison with Voriconazole

Abstract

Isavuconazole (ISZ) is used in the treatment of aspergillosis and mucormycosis. The purpose of this study was to evaluate the therapeutic drug monitoring (TDM) of ISZ samples from a clinical setting performed at Statens Serum Institut. Materials/methods: Isavuconazole serum concentrations were determined by fluorescent detection on a UHPLC. Serum-ISZ (s-ISZ) results were included and compared to those of serum-voriconazole (s-VRZ) in a 33 month period from March 2017. Clinical data were obtained for patients receiving ISZ. The therapeutic range was initially 2–10 mg/L, but was adjusted to 2–5 mg/L during the study period except for selected patients with Mucorales infections who received off-label doses of ISZ. Results: A total of 273 s-ISZ and 1242 s-VRZ measurements from 35 and 283 patients, respectively, were included. Seventeen patients had received both ISZ and VRZ with TDM within the study period. The median s-ISZ was 4.3 mg/L (0.5–15.4 mg/L) with 83% of measurements within the therapeutic index. The median s-VRZ was 2.6 mg/L (0.2–21.9 mg/L) with 67% of measurements within the therapeutic index. The median intra-/interindividual coefficient of variation (CV) was 43.4%/54.8% for ISZ compared to 53.2%/83.3% for VRZ. For patients receiving ISZ, the adverse events were mostly gastroenteric and few drug–drug interactions were observed. Furthermore, immediate change from ISZ to VRZ treatment seemed to lead to prolonged metabolism of ISZ with detection up to 35 days after discontinuation. Conclusions: The majority of patients achieved s-ISZ levels well within the therapeutic range with less intra/interindividual CV than patients receiving VRZ.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

“…Indeed, our data support this contention, even if TDM could represent a helpful tool in some specific cases. This is in agreement with the recent findings of a retrospective comparative study of TDM of isavuconazole (n = 273 samples from 35 patients) vs. voriconazole (n = 1424 samples from 283 patients) from Denmark [30], which confirmed that isavuconazole is much easier to target compared to voriconazole and concluded that the role of TDM for isavuconazole is not so compelling.…”

“…The median CL estimate (1.52 L/h) was somewhat lower than that reported in clinical trials (2.2-2.5 L/h) [26,27] and consistently lower than that observed in SOT patients (4.28 L/h). The pharmacokinetic model was reliable in predicting observed concentrations (with good precision and R 2 and low bias), and the interindividual variability on CL (64%) was in line with that reported by previous analysis (43-63%) [30].…”

Variability of Isavuconazole Trough Concentrations during Longitudinal Therapeutic Drug Monitoring

“…The inter- and intra-individual CVs for ISA Cmin of 41.5 and 30.7% that we found shows that the ISA Cmin were variable, especially between patients. Such a finding is in agreement with those of several recent real-life studies that reported inter-individual CVs ranging from 36.6 to 61.5% [ 8 , 9 , 22 , 23 ]. Similarly, the intra-individual CV of 30.7% that we found is similar to the intra-individual CVs previously reported, ranging from 28.2 to 43.4% [ 9 , 10 , 22 ].…”

Isavuconazole for COVID-19-Associated Invasive Mold Infections

“…We identified a total of 8 articles on isavuconazole TDM in various patient populations, which included overall data from 368 patients. The majority of included patients had hematological malignancy or were solid organ or hematopoietic stem cell transplant recipients, and a total of 1689 samples were taken for measurements of TDM ( Table 4 ) [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ].…”

“…The majority of patients had isavuconazole levels within what was considered a therapeutic range. The blood levels in patients with adverse events attributable to isavuconazole were similar to those without side effects [ 80 ].…”