Abstract
Background
Isavuconazole is a relatively new antifungal agent indicated for the management of various invasive fungal diseases (IFDs), including invasive aspergillosis. Information on real-world experience with isavuconazole is scarce. This retrospective observational study aimed to describe the usage of isavuconazole in clinical practice with an in-depth evaluation of individual isavuconazole exposure.
Methods
Patients treated with isavuconazole were evaluated based on retrospective data, including therapeutic drug monitoring (TDM) data and efficacy and safety data. Additionally, we calculated the individual isavuconazole exposure described by the average AUC24 over the first 7 days of treatment by means of non-linear mixed-effects modelling and compared this with the currently desired lower target AUC of 60 mg·h/L.
Results
Ninety-nine patients treated with isavuconazole were evaluated. In our real-life cohort, isavuconazole was often deployed off-label in patients with non-classical host factors and infections with non-Aspergillus and non-Mucorales species. Isavuconazole was most often chosen for its safety profile, even after prior triazole treatment with manifestations of toxicity. TDM and subsequent dosage adjustments were frequently performed. The individual average AUC24 over 7 days was above 60 mg·h/L in 29 out of 77 (37.7%) patients.
Conclusions
This overview provides practical insights that can aid clinicians in the management of their patients with IFD. Our study shows that isavuconazole was used in a diverse patient population and was well tolerated overall. Individual isavuconazole exposure reflected by the average AUC24 over the first 7 days of treatment was generally low and variable. Dosage adjustments following TDM were frequently performed. Our experience shows that isavuconazole is a feasible alternative after prior azole treatment.
Introduction
Invasive aspergillosis (IA) is a life-threatening infection primarily caused by Aspergillus fumigatus.1 While neutropenia has long been recognized as a significant risk factor for IA, particularly in patients with haematological malignancies, new risk groups have emerged in recent decades. These include non-neutropenic patients who are critically ill, such as those with severe viral pneumonia.2 Isavuconazole is recommended for treatment of IA as it demonstrates comparable efficacy to voriconazole.3,4 Managing IA can be complicated due to side effects and drug interactions, often requiring dose adjustments or switching to another triazole or a different drug class. Of all triazoles, isavuconazole has the most favourable drug–drug interaction profile.3,5
Isavuconazole can also be used for the management of invasive fungal diseases (IFDs) other than IA, such as invasive mucormycosis (IM).6 Although polyenes, like liposomal amphotericin B, are the primary treatment choice, isavuconazole presents an attractive alternative due to its comparable efficacy and reduced risk of renal toxicity. This is especially relevant for outpatient treatment since isavuconazole is available as an oral formulation.
Isavuconazole has been extensively examined in clinical trials, but there are limited real-life data on its efficacy and safety including the application of therapeutic drug monitoring (TDM). The need for TDM of isavuconazole is under debate. So far, an AUC above 60 mg·h/L was observed in patients in the pivotal isavuconazole trial.7,8 This value typically translates to an average trough concentration (Ctrough) of 2.0–4.0 mg/L, which is commonly used as the desired efficacy target when performing TDM.8,9 In addition to this clinical target, in vivo pharmacodynamic studies show that an AUC0–24/MIC ratio of 24.73 and 33.38 is associated with 50% (EI50) and 90% (EI90) survival, respectively.10 To be able to fully benefit from isavuconazole in the antifungal treatment of patients with IFD, additional information on its pharmacokinetics and pharmacodynamics is needed.
Additional pharmacokinetic knowledge can be gained from experience in the real-life setting, for example by the evaluation of individual plasma concentration data as part of routine TDM. To make full use of these rather sparse data, a novel approach using pharmacometrics can aid in gaining more robust pharmacokinetic information. In this approach, drug administration data together with these concentration data are imputed in an available mathematical model to predict an individual’s drug exposure reflected by the AUC at a given time. These results allow for direct comparison of exposure between individuals at a specific predefined timepoint. Utilizing such an approach could provide solid data that can be collated with outcome data to potentially resolve exposure–response relationships where up until today we have not been able to do so.3
This observational study was conducted to examine the usage of isavuconazole therapy in clinical practice in the broadest sense, including its model-derived prediction of individual exposure based on TDM data and its efficacy and safety.
Methods
Study design and patients
This retrospective analysis was conducted in a tertiary care university hospital in the Netherlands (Radboud University Medical Center, Nijmegen). Adult patients (≥18 years old) who received isavuconazole from May 2017 to July 2021 were included. Due to the retrospective nature of the study, we received a waiver to obtain informed consent from the local ethics committee.
Data collection
Data were collected from the patients’ medical records and included patient demographics (e.g. age, sex, body weight, underlying condition), isavuconazole treatment data (e.g. indication, route of administration, treatment duration, total daily dose, dose adjustments), safety data (e.g. hepatobiliary laboratory test results) and TDM data (e.g. Ctrough, number of samples per patient). Descriptive data on outcome were also collected. Isavuconazole treatment was considered successful when antifungal therapy was no longer needed, or as failed when discontinued due to a lack of clinical response, adverse events or death.
Diagnosis and classification
Diagnostic tests were performed when there was a suspicion of IFD (e.g. clinical signs, symptoms or imaging suggestive of IFD). In patients at risk of developing IFD, diagnostic procedures were routinely performed twice weekly. These included but were not limited to, galactomannan and (1,3)-β-D-glucan and PCR (i.e. Aspergillus, Mucorales and panfungal PCR) as well as cultures. If possible, we classified patients as cases of proven, probable or possible IFD according to the following mycology case definitions where applicable: European Organisation for Research and Treatment of Cancer, Mycoses Study Group Education and Research Consortium (EORTC/MSGERC);11AspICU;12 influenza-associated pulmonary aspergillosis (IAPA)13 and COVID-19-associated pulmonary aspergillosis (CAPA).14
Dosing and TDM
In accordance with the Summary of Product Characteristics (SmPC) of isavuconazole,15 standard dosing comprised an initial loading dose of 200 mg every 8 h for 48 h followed by a maintenance dose of 200 mg daily. Doses could be increased or decreased based on clinical indications, including toxicity, and TDM results. Decisions on dose adjustments were made in consultation with expert pharmacologists. Consistent with institution guidelines during the study period, adequate isavuconazole exposure was defined as Ctrough above 2.0–4.0 mg/L. Total isavuconazole concentrations were determined by means of a fully validated LC-MS/MS assay.
Individual drug exposure
To gain additional information on the pharmacokinetics of isavuconazole in the studied population, we calculated the isavuconazole exposure of included individuals using the sparse isavuconazole plasma concentration data. Individual isavuconazole exposure described by the AUC24 was calculated by means of post hoc estimation using non-linear mixed-effects modelling with NONMEM® (version 7.5.1) using the Perl-Speaks-NONMEM interface. For this purpose, a previously published isavuconazole population pharmacokinetic model comprising of two compartments, Weibull absorption and first-order elimination was used.16 The NONMEM control stream of this model is available in the Supplementary Materials (available as Supplementary data at JAC Online). We assessed the average AUC24 over the first 7 days of therapy to account for differences in received loading doses and for patients not yet reaching steady state. To allow calculation of the average AUC24 over 7 days for individuals who discontinued isavuconazole therapy before Day 7, dosing was carried forward, i.e. the same dose, frequency and route of administration was repeated until Day 7. For subjects without any routine TDM measurements available, additional isavuconazole plasma concentration measurements were retrospectively performed. Bias and imprecision of the post hoc estimation results were evaluated by means of a simulation and re-estimation analysis. We compared our findings with the currently used threshold AUC24 of 60 mg·h/L.7,8
Efficacy and safety
For patients where both a model-predicted average AUC24 and an MIC value were available, we calculated an AUC24/MIC ratio. We compared this with the AUC24/MIC ratio of 24.7 and 33.4 corresponding with the effective PK/PD index at 50% (EI50) and 90% (EI90) for A. fumigatus, respectively.10 Available safety laboratory data were graded using the Common Terminology Criteria for Adverse Events (CTCAE).
Ethics
The local medical ethical review board waived the necessity of formal approval and informed consent for this study.
Results
Patients
Ninety-nine patients were treated with isavuconazole. Eight patients were excluded due to age <18 years (n = 3), start of treatment in another hospital (n = 4), and an explicit statement in the patients’ medical record to be excluded from scientific research (n = 1). A summary of patient baseline characteristics is shown in Table 1. The primary underlying condition was haematological malignancy in 51 (56.0%) patients, solid organ transplant in 4 (4.4%) patients, immunosuppressive therapy for another indication in 6 (6.6%) patients, and an inherited severe immunodeficiency in 4 (4.4%) patients. Primary underlying conditions not contributing to the EORTC/MSGERC host criteria were chronic pulmonary aspergillosis or allergic bronchopulmonary aspergillosis in 10 (11.0%) patients, and severe viral pneumonia in 10 (11.0%) patients. Two patients with severe viral pneumonia were also immunocompromised (i.e. haematological malignancy and solid organ transplant).
Table 1.
Patient baseline characteristics
| Characteristic | Therapy | Prophylaxisa | Overallb |
|---|---|---|---|
| Patients, n | 69 | 28 | 91 |
| Sex, male, n (%) | 39 (56.5) | 13 (46.4) | 50 (54.9) |
| Age, years, median (range) | 61 (18–84) | 54 (26–74) | 59 (18–84) |
| BMI, kg/m2, median (range) | 24.6 (13.8–36.7) | 24.7 (16.7–32.4) | 24.8 (13.8–36.7) |
| Primary underlying condition, n (%) | |||
| Haematological malignancy | 36 (52.2) | 21 (75.0) | 51 (56.0) |
| Leukaemia | 24 (66.7) | 15 (71.4) | 33 (64.7) |
| Lymphoma | 4 (11.1) | 1 (4.8) | 5 (9.8) |
| Aplastic anaemia | 2 (5.6) | 2 (9.5) | 4 (7.8) |
| Sickle cell anaemia | 1 (2.8) | 0 (0.0) | 1 (2.0) |
| Myelodysplastic syndrome | 3 (8.3) | 2 (9.5) | 5 (9.8) |
| Polycythaemia vera | 2 (5.6) | 1 (4.8) | 3 (5.9) |
| Solid organ transplant | 4 (5.8) | 0 (0.0) | 4 (4.4) |
| Kidney recipient | 3 (75.0) | 0 (0.0) | 3 (75.0) |
| Liver recipient | 1 (25.0) | 0 (0.0) | 1 (25.0) |
| Inherited severe immunodeficiency | 2 (5.6) | 2 (7.1) | 4 (4.4) |
| Interferon-gamma production defect | 1 (50.0) | 0 (0.0) | 1 (25.0) |
| Common variable immunodeficiency | 1 (50.0) | 0 (0.0) | 1 (25.0) |
| Idiopathic CD4 lymphocytopenia | 0 (0.0) | 1 (50.0) | 1 (25.0) |
| Hyper-immunoglobulin E syndrome-like | 0 (0.0) | 1 (50.0) | 1 (25.0) |
| Immunosuppressive therapy | 3 (4.3) | 3 (10.7) | 6 (6.6) |
| Severe viral pneumonia | 10 (14.5) | 0 (0.0) | 10 (11.0) |
| Severe influenza pneumonia | 6 (60.0) | 0 (0.0) | 6 (60.0) |
| Severe COVID-19 pneumonia | 4 (40.0) | 0 (0.0) | 4 (40.0) |
| Chronic pulmonary aspergillosis | 6 (8.7) | 0 (0.0) | 6 (6.6) |
| Allergic bronchopulmonary aspergillosis | 4 (5.8) | 0 (0.0) | 4 (4.4) |
| Other | 7 (10.1) | 2 (9.5) | 9 (9.9) |
| EORTC/MSGERC host factor, n (%) | 47 (68.1) | 26 (92.9) | 67 (73.6) |
| Haematological malignancy | 36 (76.6) | 21 (80.8) | 51 (76.1) |
| Recipient of stem cell transplant | 18 (38.3) | 10 (38.5) | 25 (37.3) |
| Recipient of solid organ transplant | 4 (8.5) | 0 (0.0) | 4 (6.0) |
| Neutropenia | 20 (42.6) | 18 (69.2) | 34 (50.7) |
| Use of corticosteroids, ≥0.3 mg/kg | 10 (21.3) | 6 (23.1) | 15 (22.4) |
| Use of other immunosuppressants | 25 (53.2) | 14 (53.8) | 35 (52.2) |
| Inherited severe immunodeficiency | 2 (4.3) | 2 (7.7) | 4 (6.0) |
| Acute graft-versus-host disease | 5 (10.6) | 2 (7.7) | 6 (9.0) |
CD4, Cluster of differentiation 4; COVID-19, Corona virus disease 2019.
aProphylaxis involved either primary or secondary prophylaxis.
bSix patients received isavuconazole both as treatment and as (secondary) prophylaxis.
Diagnosis and classification
Sixty-nine patients received isavuconazole as therapy, of which 56 (81.2%) patients could be classified according to a mycology case definition. A summary of IFD characteristics is shown in Table 2. Nineteen (33.9%) of these patients were classified as proven IFD, 24 (42.9%) patients as probable IFD, and 13 (23.2%) patients without mycological evidence were classified as possible IFD. In proven/probable IFD patients, isavuconazole was deployed as therapy for IA in 29 (67.4%) patients, IM in 2 (4.7%) patients, both IA and IM in 3(7.0%) patients, and infections with other non-Aspergillus spp., including Candida spp., in 9 (20.9%) patients.
Table 2.
IFD characteristics
| Characteristic | Proven/probable | Possible | Overall |
|---|---|---|---|
| Patients, n | 43 | 13 | 56 |
| Classification of IFD, n (%) | |||
| Proven IFD | 19 (44.2) | NA | 19 (33.9) |
| Probable IFD | 24 (55.8) | NA | 24 (42.9) |
| Possible IFD | NA | 13 (100) | 13 (23.2) |
| Site of IFD, n (%) | |||
| Pulmonary | 28 (65.1) | 11 (84.6) | 39 (69.6) |
| Pulmonary plus another organa | 2 (4.9) | 0 (0.0) | 2 (3.6) |
| Neurological | 2 (4.9) | 1 (6.7) | 3 (5.4) |
| Paranasal sinuses | 3 (7.3) | 0 (0.0) | 3 (5.4) |
| Ear | 2 (4.9) | 0 (0.0) | 2 (3.6) |
| Hepatosplenal | 0 | 1 (6.7) | 1 (1.8) |
| Eye | 1 (2.4) | 0 (0.0) | 1 (1.8) |
| Soft tissue | 2 (4.9) | 0 (0.0) | 2 (3.6) |
| Disseminated | 3 (7.3) | 0 (0.0) | 3 (5.4) |
| Pathogen causing disease, n (%) | |||
| Aspergillus spp. only | 29 (67.4) | NA | 29 (51.8) |
| A. flavus | 1 (3.4) | NA | 1 (3.4) |
| A. fumigatus | 19 (65.5) | NA | 19 (65.5) |
| A. flavus + A. fumigatus | 1 (3.4) | NA | 1 (3.4) |
| A. nidulans | 1 (3.4) | NA | 1 (3.4) |
| A. niger | 1 (3.4) | NA | 1 (3.4) |
| A. terreus | 1 (3.4) | NA | 1 (3.4) |
| Aspergillus sp.b | 5 (17.2) | NA | 5 (17.2) |
| Aspergillus plus other fungi | 3 (7.0) | NA | 3 (5.4) |
| A. nidulans + Rhizopus microsporus | 1 (33.3) | NA | 1 (33.3) |
| Aspergillus sp.b + Mucorales | 1 (33.3) | NA | 1 (33.3) |
| A. flavus + Lichtheimia ramosa + R. arrhizus | 1 (33.3) | NA | 1 (33.3) |
| Non-Aspergillus spp. only | 11 (25.6) | NA | 11 (19.6) |
| Candida albicans | 1 (9.1) | NA | 1 (9.1) |
| Cladophialophora bantiana | 1 (9.1) | NA | 1 (9.1) |
| Fusarium sp. | 1 (9.1) | NA | 1 (9.1) |
| Pneumocystis jirovecii | 1 (9.1) | NA | 1 (9.1) |
| R. pusillus | 1 (9.1) | NA | 1 (9.1) |
| Rhizomucor sp. | 1 (9.1) | NA | 1 (9.1) |
| Scedosporium apiospermum | 1 (9.1) | NA | 1 (9.1) |
| Scedosporium prolificans | 1 (9.1) | NA | 1 (9.1) |
| Saprochaete clavata | 3 (27.3) | NA | 3 (27.3) |
NA, not applicable.
aOne patient with both a pulmonary and neurological IFD, and one patient with both a pulmonary and paranasal sinus IFD.
bOnly positive for bronchoalveolar lavage galactomannan, which precludes species identification.
Aspergillus was cultured from 24 patients, with additional MIC determination for 23 (95.8%) patients, which revealed susceptible Aspergillus spp. (isavuconazole MIC ≤ 1 mg/L) in 20 (87.0%) patients. Two (8.7%) patients were infected with isavuconazole-resistant Aspergillus spp. (i.e. A. fumigatus harbouring TR34/L98H mutation in the Cyp51A gene, and A. terreus with isavuconazole MIC of 4 mg/L), while one (4.3%) patient was infected with both WT and resistant A. fumigatus, harbouring the TR46/Y121F/T289A/S363P/I364V/G448S mutation in the Cyp51A gene. Mucorales spp. were cultured from three patients, with additional MIC determination for two (66.7%) patients, which revealed an isavuconazole MIC of 2 mg/L for both Lichtheimia ramosa and Rhizomucor pusillus.
Dosing and TDM
A summary of isavuconazole dosing information and reasons to select isavuconazole as treatment are shown in Table 3. Overall, in 81 (89.0%) patients isavuconazole was dosed according to the SmPC. Three (3.3%) patients received the licensed loading doses of 200 mg every 8 h for 48 h, but their maintenance dose was adjusted to 200 mg twice daily, 200 mg thrice daily, and 100 mg daily, respectively. The remaining seven (7.7%) patients received four to five loading doses of 200 mg instead of six, followed by the licensed maintenance dose of 200 mg daily. Exact reasons for these deviations from the licensed dosing regimen could not be retrieved but are likely caused by issues of practicality.
Table 3.
Isavuconazole treatment
| Therapy | Prophylaxisa | Overallb | |
|---|---|---|---|
| Patients, n | 69 | 28 | 91 |
| Dosing according to SmPC, n (%) | 58 (84.1) | 26 (92.9) | 81 (89.0) |
| Treatment duration, days, median (range) | 34 (2–648) | 59 (4–1673) | 37 (2–1673) |
| Initial oral administration, n (%) | 47 (68.1) | 26 (92.3) | 68 (74.7) |
| Initial IV administration, n (%) | 22 (31.9) | 2 (7.1) | 23 (25.3) |
| Only oral administration, n (%) | 42 (60.9) | 26 (92.3) | 62 (68.1) |
| Only IV administration, n (%) | 14 (20.3) | 2 (7.1) | 14 (15.4) |
| Oral and IV administration, n (%) | 13 (18.8) | 0 (0.0) | 15 (16.5) |
| Reason to choose isavuconazole as first-line treatment, n (%) | 18 (25.4) | 28 (100) | 45 (49.5) |
| Large spectrum of action | 3 (16.7)c | 2 (7.7) | 5 (11.1)c |
| Safety profile | 10 (55.6)c,d | 19 (65.4)e | 28 (62.2)c,d,e |
| Favourable drug–drug interaction profile | 5 (27.8)d | 8 (30.8)e | 13 (28.9)d,e |
| Other | 3 (16.7) | 1 (3.8) | 4 (8.9) |
| Reason to choose isavuconazole as second-line treatment, n (%) | 51 (73.9) | NA | 51 (56.0) |
| Intolerance therapy | 45 (88.2) | NA | 45 (49.5) |
| Salvage therapy | 6 (11.8) | NA | 6 (6.6) |
aProphylaxis involved either primary or secondary prophylaxis.
bSix patients received isavuconazole both as treatment and as (secondary) prophylaxis.
cFor two patients, isavuconazole was chosen for both its large spectrum of action and safety profile.
dFor one patient, isavuconazole was chosen for both its favourable drug–drug interaction profile and safety profile.
eFor two patients, isavuconazole was chosen for both its favourable drug–drug interaction profile and safety profile.
Isavuconazole was most often chosen as first-line treatment (i.e. primary therapy, primary prophylaxis or secondary prophylaxis) for its safety profile (62.2%). In 51 patients, isavuconazole was deployed as second-line treatment for reasons of intolerance to other antifungals in 45 (88.2%) patients and as salvage therapy in 6 (11.8%) patients. In six patients isavuconazole was first employed as therapy and thereafter as secondary prophylaxis.
Individual drug exposure
A total of 181 plasma samples were obtained from 47 (49.0%) patients for routine TDM and results are presented in Figure 1. No clear trend for reasons to perform TDM or not could be identified. Reasons to perform TDM were, among others, suspected lack of efficacy, unexplained toxicity, suspected non-compliance, admittance to the ICU, and/or obesity.
Figure 1.
Isavuconazole plasma trough concentrations determined for TDM. The horizontal broken lines represent the total isavuconazole plasma concentration of 2.0–4.0 mg/L currently recommended by international guidelines as threshold.8 Closed circles, initial measurement; open circles, subsequent measurement.
A summary of isavuconazole Ctrough measurements and dose adaptations is shown in Table 4. The median isavuconazole Ctrough was 2.54 (range, 0.45–10.0) mg/L. In 18 patients, 31 dose adjustments were made resulting in a median isavuconazole Ctrough of 3.17 (range, 0.28–10.0) mg/L.
Table 4.
TDM and dose adaptations
| Therapy | Prophylaxisa | Overallb | |
|---|---|---|---|
| Patients, n | 42 | 5 | 47 |
| Initial Ctrough measurement, days, median (range) | 6 (2–127) | 7 (3–20) | 6 (2–127) |
| Initial Ctrough, mg/L, median (range) | 2.39 (0.45–10.0) | 4.02 (1.35–7.35) | 2.54 (0.45–10.0) |
| <2.0 mg/L, n (%) | 16 (38.1) | 1 (20.0) | 17 (36.2) |
| 2.0–4.0 mg/L, n (%) | 18 (42.9) | 1 (20.0) | 19 (40.4) |
| ≥4.0 mg/L, n (%) | 8 (19.0) | 3 (60.0) | 11 (23.4) |
| C trough samples, n | 142 | 39 | 181 |
| Ctrough < 2.0 mg/L, n (%) | 31 (21.8) | 4 (10.3) | 35 (19.3) |
| Ctrough 2.0–4.0 mg/L, n (%) | 69 (48.6) | 23 (59.0) | 92 (50.8) |
| Ctrough ≥ 4.0 mg/L, n (%) | 42 (29.6) | 12 (30.8) | 54 (29.8) |
| All Ctrough, mg/L, median (range) | 3.18 (0.28–10.0) | 3.13 (1.35–7.35) | 3.17 (0.28–10.0) |
| Dose adaptations, n (%) | 14 (33.3) | 4 (80.0) | 18 (38.3) |
| Dose increase | 8 (57.1) | 2 (50.0) | 10 (55.6) |
| Dose increase at Ctrough < 2.0 mg/L | 7 (87.5) | 1 (50.0) | 8 (80.0) |
| Dose increase resulted in Ctrough 2.0–4.0 mg/Lc | 7 (100) | 1 (100) | 9 (100) |
| Dose decrease | 11 (78.6) | 4 (100) | 15 (83.3) |
| Dose decrease at Ctrough ≥ 4.0 mg/L | 11 (100) | 4 (100) | 15 (100) |
| Dose decrease resulted in Ctrough 2.0–4.0 mg/Lc | 8 (72.7) | 3 (100) | 12 (85.7) |
| Dose adaptations, n | 25 | 6 | 31 |
| Dose increases, n (%) | 11 (44.0) | 2 (33.3) | 13 (41.9) |
| Dose increases at Ctrough < 2.0 mg/L, n (%) | 9 (81.8) | 1 (50.0) | 10 (76.9) |
| Dose decreases, n (%) | 14 (56.0) | 4 (66.7) | 18 (58.1) |
| Dose decreases at Ctrough ≥ 4.0 mg/L, n (%) | 14 (100) | 4 (100) | 18 (100) |
C trough, isavuconazole plasma trough concentrations.
aProphylaxis involved either primary or secondary prophylaxis.
bSix patients received isavuconazole both as treatment and as (secondary) prophylaxis.
cAdditional samples to follow-up on a dose adjustment were not obtained for all patients.
For 77 (84.6%) patients, exposure data were available, allowing calculation of the model-predicted average AUC24 over the first 7 days of isavuconazole treatment using the model described in the Supplementary Materials. The most frequent underlying conditions in these patients were a haematological malignancy (43 patients; 55.8%) and severe viral pneumonia (8 patients; 10.4%). For 30 of these patients, no routine TDM was performed and thus isavuconazole plasma concentrations were measured in retrospect in 31 samples. Bias and imprecision of the post hoc estimation was less than ±20% and thus considered acceptable.
The model-predicted average AUC24 over the first 7 days of therapy for each individual is shown in Figure 2. The median (range) individual model-predicted isavuconazole exposure in the study population was 55.1 (37.4–124.1) mg·h/L. For 29 (37.7%) patients, the individual model-predicted average AUC24 over the first 7 days was above the predefined threshold of 60 mg·h/L.
Figure 2.
Model-predicted average isavuconazole AUC24 over first 7 days of treatment. The horizontal broken line represents the 25th percentile AUC24 of 60 mg·h/L observed in the SECURE trial.9
Efficacy
A summary of response to isavuconazole treatment in patients with IFD is shown in Table 5. Of 56 patients treated with isavuconazole for IFD, five were lost to follow-up. For the remaining 51 patients, treatment was considered successful in 30 patients (58.8%). Isavuconazole was discontinued due to a lack of clinical response in four (7.8%) patients or adverse events in three (5.9%) patients and stopped because the patient died in 14 (27.5%) cases.
Table 5.
Outcome for IFD patients treated with isavuconazole
| Primary therapy | Intolerance therapy | Salvage therapy | Overall | |
|---|---|---|---|---|
| Patients, n | 15 | 36 | 5 | 56 |
| Lost to follow-up, n | 0 | 3 | 2 | 5 |
| Proven/probable IFD, n | 9 | 26 | 3 | 38 |
| Reason for end of isavuconazole treatment, n (%) | ||||
| Successful response | 4 (44.4) | 15 (57.7) | 3 (100) | 22 (57.9) |
| Lack of response | 2 (22.2) | 1 (3.8) | 0 (0.0) | 3 (7.9) |
| Adverse events | 0 (0.0) | 2 (7.7) | 0 (0.0) | 2 (5.3) |
| Patient died | 3 (33.3) | 8 (30.8) | 0 (0.0) | 11 (28.9) |
| Possible IFD patients, n | 6 | 7 | 0 | 13 |
| Reason for end of isavuconazole treatment, n (%) | ||||
| Successful response | 2 (33.3) | 6 (85.7) | 0 (0.0) | 8 (61.5) |
| Lack of response | 1 (16.7) | 0 (0.0) | 0 (0.0) | 1 (7.7) |
| Adverse events | 1 (16.7) | 0 (0.0) | 0 (0.0) | 1 (7.7) |
| Patient died | 2 (33.3) | 1 (14.3) | 0 (0.0) | 3 (23.1) |
For 19 patients with IA, one patient with IM, and one patient with both IA and IM, both model-predicted average AUC24 and MIC values were available, allowing the calculation of an AUC24/MIC ratio. Of 19 patients with IA, the calculated AUC24/MIC ratio was below 33.4 in 2 (10.5%) patients. One of these patients was infected with A. fumigatus harbouring the TR34/L98H mutation (isavuconazole MIC 8 mg/L) and switched to voriconazole in combination with anidulafungin due to disease progression. The other patient was infected with A. terreus (isavuconazole MIC 4 mg/L) and was lost to follow-up for assessment of outcome. Of the 17 (89.5%) IA patients with an AUC24/MIC ratio above 33.4, 1 patient was lost to follow-up for assessment of outcome. Of the remaining 16 patients, 9 (56.3%) patients had successful treatment. Notably, four of these nine patients additionally received liposomal amphotericin B or anidulafungin as combination therapy. In the remaining seven (43.7%) patients, one patient switched to liposomal amphotericin B due to disease progression and six patients died.
For the patient with IM, the AUC24/MIC ratio was 26.4. This patient switched from liposomal amphotericin B to isavuconazole in combination with micafungin due to nephrotoxicity and later died. For the patient with both IA and IM, the AUC24/MIC ratio was 142.8 and 35.7 for A. flavus and L. ramosa, respectively. This patient switched from liposomal amphotericin B to isavuconazole in combination with local amphotericin B therapy due to hypokalaemia, and this treatment was considered successful.
There was a breakthrough pulmonary A. fumigatus (isavuconazole MIC 0.5 mg/L) infection in one (3.6%) patient receiving isavuconazole as primary prophylaxis. No exposure information was available for this patient and no dosage intervention was performed. Another patient had a breakthrough pulmonary IM (MIC unknown) while receiving isavuconazole as treatment for pulmonary IA. Even though an isavuconazole Ctrough of 4.4 mg/L was measured, with a corresponding calculated average AUC24 of 50.0 mg·h/L, new lesions in the opposing lung were observed on CT and a Mucorales sp. was cultured from bronchoalveolar lavage fluid. This patient additionally received liposomal amphotericin B for 10 days and the isavuconazole dose was increased to once-daily 400 mg. In both patients, treatment with isavuconazole was eventually considered successful.
Reason for selection
In the six patients who received isavuconazole as salvage therapy, this was due to suboptimal voriconazole Ctrough in four (66.7%) patients, suboptimal itraconazole Ctrough in one (16.7%) patient, and disease progression in one (16.7%) patient. Treatment was considered successful in three of these patients; the other three patients were lost to follow-up. Of 45 patients treated with isavuconazole for reasons of intolerance to other therapy, 36 (80.0%) patients were initially treated with (multiple) other azoles, eight (17.8%) patients with liposomal amphotericin B, and one (2.2%) patient with an echinocandin. Reasons to switch from other azoles were hepatotoxicity in 16 (44.4%) patients, cardiotoxicity in 5 (13.9%) patients, hallucinations in 4 (11.1%) patients, nausea/vomiting in 3 (8.3%) patients, leukopenia in 2 (5.6%) patients, rash in 2 (5.6%) patients and other (i.e. favourable drug–drug interactions, undesirable frequent TDM for voriconazole, and treatment >6 months) in 4 (11.1%) patients. Reasons to switch from liposomal amphotericin B were nephrotoxicity in seven (87.5%) patients, and hypokalaemia in one (12.5%) patient. In the only patient who switched from echinocandins to isavuconazole, this was because of hepatotoxicity, and treatment with isavuconazole was considered successful in that patient. Of 16 patients who switched from other azoles because of hepatoxicity, treatment was considered successful in 11 (68.8%) patients, while treatment was discontinued due to persistent hepatoxicity in 1 (6.3%) patient, and due to mortality in 4 (25.0%) patients. Of eight patients who switched from liposomal amphotericin B due to nephrotoxicity or hypokalaemia, treatment was considered successful in five (62.5%) patients, while treatment was discontinued due to hepatotoxicity in one (12.5%) patient, and due to mortality in one (12.5%) patient.
Safety
An overview of worst-case values of laboratory test results graded according to the CTCAE is shown in Table 6. Severe or medically significant (i.e. grade 3) or life-threatening (i.e. grade 4) increase of any hepatobiliary laboratory test results [ALT > 5 × upper limit of normal (ULN), AST > 5 × ULN, alkaline phosphatase > 5 × ULN, or total bilirubin >3 × ULN) was measured in 17 of 81 (21.0%) patients during treatment with isavuconazole, decrease of estimated glomerular filtration rate (i.e. <30 mL/min/1.73 m2) in 10 of 75 (13.3%) patients, while any electrolyte imbalances (i.e. hypokalaemia < 3.0 mmol/L or hypomagnesaemia < 0.4 mmol/L) was measured in 6 of 74 (8.1%) patients.
Table 6.
Laboratory test results at any time during isavuconazole treatment graded according to the CTCAE
| Laboratory result | Patients n |
Grade 1 n (%) |
Grade 2 n (%) |
Grade 3 n (%) |
Grade 4 n (%) |
|---|---|---|---|---|---|
| ALT increased | 76 | 26 (34.2) | 11 (14.5) | 7 (9.2) | 1 (1.3) |
| AST increased | 75 | 30 (40.0) | 7 (9.3) | 6 (8.0) | 0 (0.0) |
| Alkaline phosphatase increased | 75 | 25 (33.3) | 11 (14.7) | 8 (10.7) | 0 (0.0) |
| Bilirubin increased | 74 | 10 (13.5) | 7 (9.5) | 5 (6.7) | 0 (0.0) |
| Estimated glomerular filtration rate (CKD-EPI) decreased | 75 | 28 (37.3) | 15 (20.0) | 7 (9.3) | 3 (4.0) |
| Hypokalaemia | 74 | 20 (27.0) | 0 (0.0) | 4 (5.4) | 1 (1.4) |
| Hypomagnesaemia | 52 | 17 (32.7) | 3 (5.8) | 3 (5.8) | 0 (0.0) |
CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
Discussion
This retrospective observational study describes the use of isavuconazole in a real-life cohort with an in-depth evaluation of individual isavuconazole exposure. Our observations show that in clinical practice, isavuconazole is used in a diverse patient population and for a variety of fungal pathogens. Treatment with isavuconazole was well tolerated overall in our cohort. Yet, its exposure was variable and dosage adjustments were frequently performed. This overview can aid clinicians in the management of their patients with IFD by providing practical insights for alternative treatment with isavuconazole.
Most patients received isavuconazole for treatment of IA and/or IM. However, we observed that isavuconazole was also used for a wide variety of non-Aspergillus and non-Mucorales infections. This included Candida spp. infections, where echinocandins are considered the primary treatment option.17 Little over half of patients receiving isavuconazole had classical host factors. Further to this, isavuconazole was also frequently deployed in patients with severe viral pneumonia admitted to the ICU. This reflects the emerging rates of IFD in this critically ill population that have been reported recently.2 Notably, a number of patients received isavuconazole for prophylaxis of IFD while this indication is not in the label. Future in-depth qualitative studies could focus on argumentation behind clinicians’ preferences for isavuconazole over other triazoles.
Two major concerns related to the use of triazoles are that of treatment-related toxicity, mainly hepatotoxicity, and drug–drug interactions.3,4,18 Compared with the other triazoles, isavuconazole has a favourable drug–drug interaction profile and results in fewer adverse effects.3 The observations in our cohort underline these assumptions. In over 90% of patients, isavuconazole was selected when other triazoles were considered unsafe or causing drug–drug interactions with concomitantly administered agents. Nonetheless, our safety analysis points towards some issues of treatment-related toxicity with isavuconazole since grade 3 and 4 adverse events, mainly increase of hepatobiliary test results, were observed. Due to the retrospective nature of our study, a direct causal relationship between the use of isavuconazole and these events cannot be established. Other coadministered drugs may have contributed to this observed toxicity and events could also be related to the course of the disease. Importantly, the observed percentages of adverse events were similar to what has been reported in the SECURE study, and were generally lower than reported for voriconazole.3 Almost 90% of patients received isavuconazole as second-line therapy after being confronted with intolerance to other antifungals. We learned that it is feasible to switch to isavuconazole after prior antifungal treatment, including other triazoles, without interruptions.
TDM was performed in more than half of the patients included in our cohort. From our retrospective analysis, no clear trend for reasons to perform TDM or not could be identified. Frequent dosage adjustments were performed as required according to the, at that time, proposed targets. These observations further emphasize the ongoing debate on the need for TDM of isavuconazole. A novelty of our study is the in-depth evaluation of the isavuconazole exposure by means of the model-derived AUC24 per individual. This allowed us to compare pharmacokinetic exposure in our cohort with that observed in patients in the pivotal isavuconazole trials. Our findings suggest that exposure in our cohort was overall lower than that observed in the SECURE trial. We can think of multiple reasons for this. One reason could be that, contrary to this trial, part of our cohort consisted of critically ill patients who are known to be prone to lower exposure.19 Another reason could be that the available data forced us to calculate the average AUC24 over the first 7 days of therapy. Steady-state AUC24 may have been somewhat higher, although it is not expected to be above 60 mg·h/L for the majority of patients.
The calculation of the individual AUC24 did not only provide additional information on isavuconazole exposure in our cohort, but also allowed us to explore the AUC24 in relation to the previously reported AUC24/MIC ratios for effective treatment of IA based on animal studies. Of course, it should be acknowledged that direct translation from animal targets to humans should be done with caution given the expected differences, including the complexity of the host immune system, differences in perfusion to the site of the infection, presence of comorbidities, etc. This is further exemplified by the fact that some patients in our cohort with higher isavuconazole exposure died, while others with lower exposure were considered to have successful clinical outcome. However, we believe it is valid to use these in vivo targets in the absence of human targets. In this respect, it is important to note that we made use of a pharmacodynamic index derived from studies with A. fumigatus isolates. It is not yet well characterized how the MICs of other species, for example those belonging to the Mucorales, correlate with that of Aspergillus species. Also, we were not able to perform an analysis over a wide MIC distribution, as the MICs of most pathogens isolated in our cohort were in the susceptible range. Nevertheless, with our analyses we have laid a foundation for integrating pharmacometric data with outcome data to explore isavuconazole exposure–response relationships. Future studies are needed to resolve these relationships that have not been fully identified to date.3
In conclusion, this detailed description of isavuconazole use in clinical practice showed that isavuconazole was more widely used than expected in terms of treated patient populations and targeted pathogens. Isavuconazole exposure appeared to be variable and frequently required dosage adjustments in our cohort. Clinicians should be aware that isavuconazole may be a viable option in patients previously treated with other antifungals despite prior manifestations of toxicity. From our findings, we conclude that isavuconazole is a valuable alternative drug choice in a broad patient population.
Supplementary Material
Acknowledgements
We would like to thank Dr. Rob ter Heine for his contribution to this study.
Contributor Information
Mehmet Ergün, Radboudumc—CWZ Center of Expertise for Mycology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Anouk M E Jansen, Radboudumc—CWZ Center of Expertise for Mycology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
Luuk B Hilbrands, Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
Elizabeth de Kort, Radboudumc—CWZ Center of Expertise for Mycology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Haematology, Radboud University Medical Center, Nijmegen, The Netherlands.
Henricus Kunst, Department of Otorhinolaryngology, Dutch Academic Alliance Skull Base Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Otorhinolaryngology, Dutch Academic Alliance Skull Base Pathology, Maastricht University Medical Center+, Maastricht, The Netherlands.
Monique H E Reijers, Radboudumc—CWZ Center of Expertise for Mycology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pulmonology, Radboud University Medical Center, Nijmegen, The Netherlands.
Jeroen A Schouten, Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Scientific Centre for Quality of Healthcare (IQ healthcare), Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
Paul E Verweij, Radboudumc—CWZ Center of Expertise for Mycology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Roger J M Brüggemann, Radboudumc—CWZ Center of Expertise for Mycology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
Funding
The current work was supported through an unrestricted grant from Pfizer Inc.. Pfizer was not involved in the conduct nor the analysis of this trial.
Transparency declarations
P.E.V. received grants through institution contracts from F2G and Gilead Sciences, received honoraria for lectures paid to institution from F2G, Gilead Sciences and Pfizer, and participated on a Data Safety Monitoring Board or Advisory Board for F2G with payment through his institution. R.J.M.B. has served as consultant to Astellas Pharma, Inc., F2G, Amplyx, Gilead Sciences, Merck Sharp & Dohme Corp., Mundipharma and Pfizer, Inc., and received unrestricted research grants from Astellas Pharma, Inc., Gilead Sciences, Merck Sharp & Dohme Corp. and Pfizer, Inc. All contracts and payments were through his institution. E.K. received an unrestricted research grant from Gilead Sciences and has served as a consultant and lecturer for Pfizer. All contracts and payments were through her institution. The other authors have no conflict of interest for the current work.
Supplementary data
Supplementary Materials are available as Supplementary data at JAC Online.
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