Isavuconazole use and TDM in real-world pediatric practice

Invasive fungal infections (IFI) mainly affect immunocompromised or critically ill children, especially patients with hematological malignancies or who have received a stem cell transplant (SCT) or solid organ transplant (SOT). Despite the latest medical advances in the field, it is still an important cause of morbidity and mortality in this population, and its diagnosis and treatment remain challenging (1–3).

Isavuconazole (ISA) is a broad-spectrum triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis in adult patients (4, 5). Its safety profile and risk for pharmacological interactions seem to be better than with L-amphotericin B (L-Amb) and voriconazole (VRC), respectively, making it an interesting alternative for the treatment of IFI (4–6). Routine therapeutic drug monitoring (TDM) may not be necessary for ISA in most instances, as ISA presents a linear pharmacokinetic profile in adult studies (4, 5, 7). Nevertheless, subsequent studies have found disparities in drug levels in critically ill patients, obese patients, children, or patients with moderate liver failure (8–10).

To date, the use of ISA in children remains off-label, as there are only a few observational studies in pediatrics, and optimal dosing and the need for TDM in children are unclear (11). At the time of writing, a clinical trial on the use of ISA in pediatric patients is ongoing with recruitment completed; however, the results are still pending publication (ClinicalTrials.gov identifier: NCT03241550; available at https://clinicaltrials.gov/ct2/show/NCT03241550. Accessed 30 January 2023).

This study aimed to describe the use of ISA and the usefulness of TDM in a real-world pediatric setting in a tertiary-care pediatric hospital.

We conducted a retrospective observational study in the Children’s Hospital at the Vall d’Hebron Barcelona Hospital Campus, a tertiary-care referral center in Barcelona (Catalonia, Spain). The local Clinical Research Ethics Committee approved the study in October 2021 [EOM(AG)056/2021(5887)].

All pediatric (≤18 years) patients who received intravenous or oral ISA for IFI treatment from June 2018 to August 2021 were included.

ISA was indicated as off-label use according to the treating physician’s criteria. ISA dosages were adjusted according to patient weight: patients weighing 35 kg or less received initial doses of 5.4 mg/kg/day (up to a maximum of 200 mg) of ISA, whereas patients weighing more than 35 kg received initial doses of 200 mg/24 h of ISA (12). All patients received a loading dose, which consisted of a target dose every 8 h during the first 48 h of treatment, followed by a maintenance dose once daily. The same dosages were maintained when patients were switched from intravenous to oral route.

Initial plasma trough levels (C_trough) were measured just before the next infusion/intake and after at least 5 days of treatment, with weekly monitoring recommended thereafter (13). These levels were determined by ultrahigh-performance liquid chromatography (Nexera X2, Shimadzu Corporation, Tokyo, Japan) with a fluorescence detector. The target for ISA plasma C_trough was 2.5–5 mcg/mL (14), and recommendations for dose adjustment were provided by the pharmacy department assuming linear pharmacokinetics (PK). Due to the limited data in clinical practice, dose escalations or dose decreases were only performed successively and modified individually as analyzed by continuous drug monitoring.

IFI classification and response to treatment were defined according to the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) 2019 definitions (15). Clinical and radiological response to treatment was evaluated only in proven and probable IFI at 6 and 12 weeks and end of treatment, irrespective of the first antifungal choice (15). We considered complete, partial, or stable response to be successful, as stabilization of fungal disease during periods of severe immunocompromise may provide evidence of treatment efficacy (16). The final outcome was defined for all patients as vital status (death or alive) at IFI resolution or at the end of the study period, whichever occurred first. Adverse events (AEs) were collected from medical records, reviewing possible liver, skin, and cardiovascular toxicities as well as infusion-related reactions attributed to ISA as per the treating physician’s evaluation and classified according to the Common Terminology Criteria for Adverse Events v5.0 (17).

The statistical analysis was performed by the Statistics and Bioinformatics Unit at the Vall d’Hebron Research Institute. All analyses were performed using the statistical software “R” (R version 4.2.0 [2022-04-22 ucrt], R Foundation for Statistical Computing).

During the study period, 15 patients (15 IFI episodes) received treatment with ISA for suspected fungal infections. Median (interquartile range [IQR]) age and weight were 13 (6–14) years and 35 (22–57.6) kg, respectively.

Proven and probable IFI were diagnosed in five and three patients, respectively, and Aspergillus spp. was the main causative pathogen (6/8). Complete information on patient and IFI characteristics is shown in Table 1.

Isavuconazole was indicated as second-line or salvage therapy in most cases (10/15). The main reasons for ISA indication were toxicity to previous antifungals (9/15) and a better safety profile as first-line treatment (4/15). Most patients (13/15) received ISA as a part of a combined antifungal therapy. The median total duration of ISA treatment was 51 days (IQR 14–219). Two patients received ISA for more than 2 years (until complete IFI resolution and lung retransplant, respectively). All patients but one initiated treatment with ISA intravenously, and six were switched to the oral route during treatment.

The median daily dose in non-ECMO patients was 5.7 mg/kg/day (IQR 5.45–6.56 mg/kg/day) in those weighing ≤35 kg and 200 mg/day in those weighing >35 kg. Individual daily dosages are shown in Table 2.

TDM was performed in all patients (median two levels/patient, range 1–30), obtaining 111 ISA C_trough levels. The median time to the first ISA C_trough sampling was 9 days (IQR 7–11). Overall, 52/111 (46.8%) C_trough determinations were outside the therapeutic range (34/111 [30.6%] subtherapeutic and 18/111 [16.2%] supratherapeutic). The median ISA C_trough was 3.1 mcg/mL (IQR 2.4–4.5).

Overall, 9/15 initial ISA C_trough measurements were out of therapeutic range (6/15 subtherapeutic and 3/15 supratherapeutic) as reported in Table 2. The differences between median C_trough during intravenous and oral administration (3.0 mcg/mL [IQR 2.4–4.2] versus 3.6 mcg/mL [IQR 2.5–4.6], P = 0.406) were not significant, with both within the therapeutic range.

Age or weight were not related to overall C_trough levels (Pearson’s correlation coefficient for overall C_trough 0.067 [95%CI –0.12 to 0.25] for age and –0.039 [95%CI –0.22 to 0.149] for weight).

TDM led to dosage adjustments in 6/15 patients (four of them more than once), with 32 total dosage adjustments during the study period.

In the case of ISA TDM in patients receiving ECMO, a total of 29 C_trough determinations were performed in three patients (patients 1, 5, and 14) during ECMO support. Patient 1 was initially on ECMO for 73 days, and ISA was initiated on day +15 due to disseminated aspergillosis (18). She needed higher dosages during ECMO to maintain the levels in range (median dose of 9.5 mg/kg/day during ECMO compared to 5.9 mg/kg/day without ECMO), with similar median C_trough during ECMO compared to after ECMO support (3.1 mcg/dL [IQR 2.3–8.1] versus 4.4 mcg/dL [IQR 3.6–5.6], P = 0.333). Similarly, patient 15 needed higher dosages during ECMO (14.5 mg/kg/day with ECMO versus 5.4 mg/kg/day without ECMO) to maintain similar levels (median C_trough 2.8 mcg/dL before ECMO, IQR 2.4–3.3 mcg/dL, and 3 mcg/dL [IQR 2.7–5.3] during ECMO; P = 0.377). Patient 5 only received ISA for 1 week after lung transplantation that required ECMO support after surgery. TDM was performed just once as the patient unfortunately died due to IFI progression and massive bleeding. Complete TDM data are presented in Table 2.

Treatment response was favorable in 4/8 patients with proven or probable IFI at the end of treatment (the other four patients died, and two of them attributed to IFI progression). Two patients (patients 14 and 15) received ISA as monotherapy throughout the entire study period: one presented a partial response at the end of the study period, and the other died due to his underlying disease.

Throughout the study period, only one patient (patient 3) had an adverse event attributed to ISA: mildly increased liver enzymes (grade 1 AE, peak levels of aspartate aminotransferase 100 IU/L, and alanine aminotransferase 213 IU/L) leading to ISA withdrawal although the C_trough levels were subtherapeutic. This patient had previously experienced severe liver graft-versus-host disease.

The present study reports on our experience with ISA use in a real-world setting in a tertiary-care children’s hospital. This study is the first to include pediatric patients with nonhematological conditions, some receiving ECMO.

Our data support the need for TDM in pediatric settings, as half the C_trough determinations were outside of the therapeutic range, especially initial C_trough, even though all patients had initial C_trough determinations after 5 days of treatment once a steady state had been reached. However, the median C_trough was within the therapeutic range (3.1 mcg/mL), probably due, at least in part, to dosage adjustments following TDM.

Throughout the study period (including TDM-guided changes), the median ISA dose in patients < 35 kg (excluding patients under ECMO support) was similar to the initial doses established in all patients, suggesting that initial doses of 5.4 mg/kg/day may usually be adequate to attain therapeutic levels. Some studies used 100 mg/day in patients < 30 kg and 200 mg/day in patients > 30 kg (11, 19). But our results suggest that younger patients may be dosed by kg as higher doses may be needed.

Overall, we found no relationship between ISA C_trough and weight or age in our group, in contrast with Decembrino et al. (19) who found that younger patients had high drug clearance and, therefore, proposed higher dosages in younger patients.

In our cohort, ISA was switched to the oral route in six patients who continued with similar C_trough levels, consistent with previous data demonstrating a very high oral bioavailability in both adults and children (20–22).

Patients receiving ECMO therapy were analyzed separately. Interestingly, patients 1 and 14 were receiving ECMO support only for part of the time they were receiving ISA treatment, allowing us to demonstrate the need for higher dosages under ECMO support to attain levels within range. This could be explained by previously described PK changes during ECMO support, mainly due to an increased volume of distribution (more accentuated in children), variations in drug clearance, and drug sequestration within the ECMO circuit and components. While ECMO significantly affects the VRC plasma levels and strict TDM is required (23), there are scant data on ISA during ECMO to suggest the need for increased dosages during ECMO (7, 18, 24–26). Hence, ISA TDM in this setting is generally recommended (8), as we saw in our cohort, in which patients receiving ECMO support were those who required more dosage adjustments.

Favorable ISA response to treatment (4/8) was similar to that observed in other pediatric studies (11, 19, 27). However, because ISA was administered as a second-line treatment or in combination with other antifungals in many cases, efficacy cannot be properly evaluated in our study. Our results showed very few ISA-related adverse events, providing evidence of the drug’s good safety profile in children similar to previous pediatric studies (11, 19, 22). However, we only reported AEs that clinicians attributed directly to ISA, thus potentially underestimating mild-to-moderate AEs. Another limitation is that we were unable to retrospectively collect data on possible drug interactions, major organ failure, ECMO circuit changes, or renal replacement therapy.

In conclusion, our data present the use of ISA in a real-world pediatric setting. Our results corroborate the proposed initial dosages of 5.4 mg/kg/day in patients who weigh less than 35 kg and adult dosages of 200 mg/day in patients who weigh more than 35 kg, with oral dosage forms being a good option for stable patients. Additionally, our data support that children, especially those receiving ECMO, could benefit from early and systematic TDM, as the initial dosage is not well defined and a high proportion of C_trough results, especially initial C_trough, were outside the therapeutic range. Moreover, pediatric patients receiving ECMO would probably require higher dosages and strict TDM. Nevertheless, further studies are needed to evaluate ISA efficacy and safety and to evaluate TDM in pediatric settings.

We would like to thank the Statistics and Bioinformatics Unit of the Vall d’Hebron Hospital Research Institute for the statistical analysis. We also thank Helen Casas and Laura Casas for their English language support. Finally, we would especially like to thank all participating patients and their families.