Achievement of clinical isavuconazole blood concentrations in transplant recipients with isavuconazonium sulphate capsules administered via enteral feeding tube

Abstract

Background

Isavuconazole is a triazole antifungal available in IV and capsule formulation. Prescribing information states that capsules should not be chewed, crushed, dissolved or opened because the drug was not studied in this manner. However, considering the pharmacokinetics of the capsules, we theorized opening and sprinkling the contents into an enteral feeding tube (EFT) would result in adequate absorption and systemic concentrations of isavuconazole.

Objectives

To determine whether patients receiving isavuconazonium sulphate capsules via EFT would achieve clinical blood concentrations of isavuconazole.

Methods

Nineteen solid organ and HCT recipients receiving isavuconazole via EFT for prevention or treatment of invasive fungal infection (IFI) were prospectively identified at four academic medical centres in the USA. Patients were included in this evaluation if they received isavuconazole via EFT for at least 5 days and therapeutic drug monitoring (TDM) was performed.

Results

TDM was performed after a median of 7 days (range 6–17) following EFT administration and 15 days (range 7–174) of isavuconazole therapy overall. Median isavuconazole concentration was 1.8 μg/mL (range 0.3–5.2). Median isavuconazole concentrations in patients with or without prior IV administration were 1.8 μg/mL (range 0.3–5.2) and 2.2 μg/mL (range 0.8–3.6; P = 0.896), respectively. Concentrations achieved with the EFT route were similar to or greater than the corresponding concentrations via the IV route in six patients who had TDM performed during both routes of administration.

Conclusions

It is reasonable to consider opening isavuconazonium sulphate capsules and administering the contents enterally for prevention and treatment of IFI.

Introduction

Isavuconazole is a triazole antifungal agent with FDA approval for the treatment of invasive aspergillosis and mucormycosis.¹ It is available in IV and capsule formulations. The capsule product consists of isavuconazonium sulphate, a prodrug of isavuconazole, and a coating composed of magnesium citrate, microcrystalline cellulose, talc and other inactive ingredients that dissolve in the human intestine in an immediate-release fashion. Isavuconazonium sulphate is degraded by esterases in the small intestine to the active form, which is readily absorbed (98% bioavailability).¹ Absorption of isavuconazole is not dependent on gastric acidity or administration with food and occurs primarily in the small bowel.² While the exact location for absorption is unknown, the process likely occurs in the jejunum due to the low solubility and high permeability of isavuconazole. Isavuconazole prescribing information states capsules should not be chewed, crushed, dissolved or opened because the drug was not studied in this manner, thereby limiting patients unable to take medications by mouth to the IV formulation.²

Enteral administration of antimicrobials has several advantages over IV, including a lower risk of secondary catheter-related infections and decreased utilization of healthcare resources. Importantly, oral agents that achieve adequate systemic exposures have been shown to be as effective as IV therapy for severe infections^3,4 and, in Phase 3 trials, oral isavuconazole was used interchangeably with IV.^5,6 Considering the benefits of enteral therapy and the pharmacokinetics of the capsules, we theorized that opening an isavuconazonium sulphate capsule and sprinkling the contents into an enteral feeding tube (EFT) would result in adequate absorption and systemic concentrations of isavuconazole.

Patients and methods

Solid organ and HCT recipients receiving isavuconazonium sulphate capsules via EFT for prophylaxis or treatment of invasive fungal infection (IFI) were prospectively identified at four academic medical centres in the USA from May 2017 to November 2019. Isavuconazole administration via EFT was considered standard of care at each participating institution for patients who met the criteria outlined in Table 1. A collaborative discussion with primary medical team(s), the infectious diseases consult service and infectious diseases pharmacy specialists occurred before isavuconazole via EFT was ordered. All patients receiving isavuconazole via EFT had therapeutic drug monitoring (TDM) performed if they were anticipated to continue EFT administration for 1 week or longer. Nurses were instructed to open and sprinkle capsule contents as they would normally administer medications via EFT (i.e. the process was not standardized but rather performed within the scope of usual practice). Mixing capsule contents with tube feed formulations, water, and/or other medications was permitted.

Table 1.

Criteria for isavuconazole administration via EFT

Patients eligible for EFT	Select reasons for ineligibility
Tolerating clear liquid or more advanced diet OR tolerating enteral feeding at goal rate OR receiving other medications via EFT Haemodynamically stable Heart rate ≤100 beats per minute Systolic blood pressure ≥90 mmHg Temperature ≤100°F or 37.8°C for at least 24 h	Taking medications by mouth Severe nausea, vomiting, diarrhoea Grade III or IV mucositis Strict NPO Patient refuses oral medications Active GI bleed Ileus or suspected ileus Known malabsorption syndrome Proximal resection of small intestine Enteral tube output >500 mL/day or requiring continuous GI suction Receiving norepinephrine, epinephrine, dopamine, dobutamine or phenylephrine

NPO, nothing by mouth.

Patients were included in this evaluation if they received isavuconazole via EFT for at least 5 days and TDM was performed. Isavuconazole assays were performed by reversed-phase UPLC/MS/MS at Viracor Eurofins, Inc. (Lee’s Summit, MO, USA) and the University of Wisconsin clinical laboratory, or by HPLC-fluorescence at the University of Pittsburgh clinical laboratory. Assay ranges were 0.1–10 μg/mL (Viracor, University of Wisconsin) and 0.1–9 μg/mL (University of Pittsburgh). Neither assay has been cleared or approved for diagnostic use by the US FDA.

Demographic variables including age, sex, BMI, solid organ or HCT type and indication were collected from the electronic health record. Results of TDM, clinical outcomes through at least 60 days of EFT administration (Table 2) and EFT type, rate and location of termination were also documented. Blood levels after EFT administration of patients who previously received IV therapy (n = 13) were statistically compared with those who had no IV medication exposure (n = 6) using the Mann–Whitney U-test.

Table 2.

Description of cases of isavuconazole administered via EFT

Patient	Age (years), sex	BMI (kg/m2)	Transplant type indication induction	ISA indication	ISA start date, (IV or PO)	IV load?a	IV doses received prior to EFT conversion	Enteral doses received prior to TDM	Time of blood concentration from last dose (h)	ISA level while receiving via EFT (μg/mL)	EFT formulation and rate	EFT terminal end	Clinical outcomes and special notes
UPMC-1	68, M	22.0	DLTx ILD basiliximab	prophylaxis	POD 1	yes	8	4 (EFT), 3 (PO)	23	1.90	Impact peptide 1.5 55 mL/h	duodenum	A. nidulans isolated on 6 month bronchoscopy, transitioned from ISA to caspofungin for treatment. No susceptibility testing performed on isolate.
UPMC-2	35, F	35.7	DLTx ILD, PAH basiliximab	prophylaxis	POD 53	no	0	17	20	0.80	Vital 65 mL/h (15 h/day)	gastric +  jejunum	Completed prophylaxis, no IFI at 6 months.
UPMC-3	43, M	25.3	DLTx IPF alemtuzumab	prophylaxis	POD 63	no	0	7	23	1.10	Isosource 1.5 40 mL/h	gastric +  jejunum	Transitioned to voriconazole after 20 days ISA due to nausea.
UPMC-4	55, F	18.3	DLTx SSc, ILD, PAH basiliximab	treatment	POD 26	no	5	7	21.75	1.60	Pivot 1.5 50 mL/h	duodenum	Aspergillus fumigatus isolated from explanted lung. ISA MIC = 2 μg/mL, POS MIC >16 μg/mL. Also had ISA IV level = 1.5 μg/mL. Died 6 months post-transplant from disseminated Mycobacterium abscessus.
UPMC-5	66, F	17.3	SLTx COPD alemtuzumab	prophylaxis	POD 1	yes	30	9	19	1.70	Isosource 1.5 35 mL/h	duodenum	Completed prophylaxis. No IFI at 1 year. Also had ISA IV level = 1.7 μg/mL.
UPMC-6	45, F	25	DLTx ILD basiliximab	prophylaxis	POD 1	yes	19	7	8.33	0.30	None (feedings held)	gastric +  jejunum	Completed prophylaxis. Concern for IFI at 9 months post-transplant, ISA resumed empirically, no documented infection. Also had ISA IV level = 0.3 μg/mL.
UPMC-7	63, F	30.3	SLTx COPD alemtuzumab	treatment	>1 year	yes	27	7	23.50	1.60	Peptamen Intense 50 mL/h	pylorus/ duodenum	Treatment for A. fumigatus completed. Also had ISA IV level = 1.6 μg/mL.
UPMC-8	61, M	30.6	DLTx IPF alemtuzumab	prophylaxis	POD 0	no	0	13	24	1.60	Peptamen Intense 75 mL/h	gastric	ISA changed to itraconazole at discharge due to insurance.
UPMC-9	55, M	24.5	DLTx IPF basiliximab	prophylaxis	POD 0	yes	19	7	20.25	2.40	Nepro 65 mL/h	gastric	Completed prophylaxis, no IFI at 1 year.
UPMC-10	41, M	37.3	DLTx ILD alemtuzumab	prophylaxis	POD 0	yes	37	6	7.50	1.80	Impact 1.5 50 mL/h	proximal stomach/tip of duodenum	Completed prophylaxis, no IFI. Died at home due to cardiac arrest 8.5 months post-transplant.
UPMC-11	23, M	20.8	DLTx bronchopulmonary dysplasia basiliximab	treatment	>1 year	yes	6	6	24	5.20	Nepro 50 mL/h	gastric fundus	IFI ruled out, patient died of persistent chronic rejection and progressive respiratory failure 50 days after ISA initiation.
UPMC-12	54, M	19	DLTx coalworker’s pneumoconiosis basiliximab	prophylaxis	POD 13	no	3	7	23.50	1.60	Nepro 95 mL/h	duodenum	No IFI at 90 days.
UW-1	59, F	21.8	LTx AIH and PSC dexamethasone	treatment	POD 14	no	5	6	24	1.90	Novasource Renal 35 mL/h	duodenum	Completed treatment for fungal sinusitis. No recurrence of IFI.
UW-2	66, M	26.8	LTx HepC, HCC dexamethasone	treatment	POD 10	no	0	7	24	2.90	Novasource Renal 40 mL/h	duodenum	Treatment for pulmonary/disseminated A. fumigatus. Patient discharged to hospice, died 91 days after ISA initiation.
UW-3	29, M	21.4	3rd LTx PSC dexamethasone	treatment	prior to transplant	no	14	7	23	3.50	Vivonex 50–90 mL/h	proximal jejunum	Receiving ISA for Aspergillus terreus treatment pre-transplant. Completed treatment post-transplant. No recurrence of IFI.
MIAMI-1	56, F	19.3	alloMUD primary myelofibrosis Flu/Bu/ATG	treatment (744 mg ISA daily)	POD 313	no	7	6	22.75	1.60	Vital 1.5 45 mL/h	gastric	Receiving ISA for A. calidoustus treatment (ISA MIC = 2 μg/mL). Also had ISA 744 mg IV, daily level = 1.8 μg/mL. Serum galactomannan negative after 12 weeks of ISA, micafungin, amphotericin B, terbinafine treatment.
UCLA-1	62, M	18.6	DLTx IPF basiliximab	prophylaxis	POD 34	yes	8	10	∼24	3.10	Nepro 90 mL/h (8 h/day)	gastric  + jejunum	No IFI at 90 days. Also had ISA IV level = 1.3 μg/mL.
UCLA-2	58, F	21.5	DLTx constrictive bronchiolitis basiliximab	prophylaxis	POD 35	no	0	7	∼24	3.60	Osmolite 1.5 90 mL/h (13 h/day)	proximal jejunum	No IFI at 90 days.
UCLA-3	63, F	18.6	SLTx COPD basiliximab	prophylaxis	POD 23	no	0	7	24.50	2.80	Jevity 1.5 55 mL/h	gastric	No IFI at 60 days.

AIH, autoimmune hepatitis; alloMUD, allogeneic HSCT, matched unrelated donor; DLTx, double lung transplant; F, female; Flu/Bu/ATG, fludarabine/busulfan/ thymoglobulin; HCC, hepatocellular carcinoma; HepC, hepatitis C; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; ISA, isavuconazole; LTx, liver transplant; M, male; MIAMI, University of Miami Sylvester Comprehensive Cancer Center; NA, not applicable; PAH, pulmonary hypertension; POD, post-operative day; POS, posaconazole; PSC, primary sclerosing cholangitis; SLTx, single lung transplant; SSc, systemic scleroderma; UCLA, University of California-Davis Health; UPMC, University of Pittsburgh Medical Center; UW, University of Wisconsin Health.

^aIV load = 372 mg isavuconazonium IV every 8 h for 6 doses.

Results

Nineteen patients were included in the study (Table 2). Seventy-nine percent (15/19), 16% (3/19) and 5% (1/19) of patients were lung, liver and HCT recipients, respectively. Fifty-three percent (10/19) of patients were male and the median age was 56 years (range 23–68). Isavuconazole was prescribed for prophylaxis in 63% (12/19) and for treatment in 37% (7/19) of patients. Isavuconazole was initiated at various times in this patient population, ranging from immediately post-transplant to greater than 1 year from transplant date. Thirteen patients (68%) received IV isavuconazole prior to EFT administration; eight of these patients received a loading regimen (372 mg isavuconazonium sulphate every 8 h for six doses) while five received only maintenance dosing (372 mg isavuconazonium sulphate every 24 h). One patient’s dose (MIAMI-1, Table 2) was increased to 744 mg IV every 24 h after 132 days of standard isavuconazole therapy [372 mg by mouth (PO) or IV every 24 h] for treatment of Aspergillus calidoustus with an isavuconazole MIC of 2 μg/mL. The patient had an isavuconazole concentration of 0.5 μg/mL while receiving 372 mg PO every 24 h (capsules swallowed whole). After 28 days of high-dose IV therapy (level 1.8 μg/mL), the patient was transitioned to 744 mg isavuconazole via EFT every 24 h thereafter (level 1.6 μg/mL).

TDM was performed after a median of 7 days (range 6–17) following EFT administration and 15 days (range 7–174) of isavuconazole therapy overall. Median isavuconazole concentration was 1.8 μg/mL (range 0.3–5.2), which was drawn between 20 and 24 h after the previous dose (trough) in 16 (84%) patients. The remaining three patients had levels drawn at 7.5, 8.3 and 19 h after the previous dose. Median isavuconazole concentrations in patients with or without prior IV administration were 1.8 μg/mL (range 0.3–5.2) and 2.2 μg/mL (range 0.8–3.6; P = 0.896), respectively. Among those with prior IV administration, median isavuconazole concentrations in patients who received an IV loading dose versus no loading dose were 1.8 μg/mL and 1.6 μg/mL, respectively. Interestingly, TDM results for EFT were all similar to or greater than the corresponding IV level for six patients who had TDM performed during both routes of administration: 1.6 versus 1.5 μg/mL (UPMC-4); 1.7 versus 1.7 μg/mL (UPMC-5); 0.3 versus 0.3 μg/mL (UPMC-6); 1.6 versus 1.6 μg/mL (UPMC-7); 1.6 versus 1.8 μg/mL (MIAMI-1); and 1.3 versus 1.3 μg/mL (UCLA-1) for EFT versus IV, respectively. The patient with an IV and EFT isavuconazole level of 0.3 μg/mL (UPMC-6) was receiving concomitant phenytoin (a strong CYP3A4 inducer, known to decrease blood concentrations of isavuconazole) and had subtherapeutic levels of voriconazole prior to initiation of isavuconazole.

Of patients receiving EFT isavuconazole for prophylaxis (n = 12), one patient (UPMC-1, level 1.9 μg/mL) had Aspergillus nidulans isolated on a 6 month surveillance bronchoscopy and was transitioned from isavuconazole to caspofungin for treatment. Six of the 7 (86%) patients receiving isavuconazole for treatment had treatment success, which was determined by the infectious diseases consult service. In the entire cohort, one patient discontinued isavuconazole due to nausea (UPMC-3, level 1.1 μg/mL) and one patient transitioned to itraconazole due to outpatient insurance coverage (UPMC-8). A median of 19 days inpatient IV therapy were saved per patient (range 4–180), totalling 577 doses or $90 190.87 in medication cost avoidance for the cohort based on average wholesale price of 372 mg IV solution ($378.47) and oral capsules ($222.16).⁷ Seven patients were spared the need for peripherally inserted central catheters (PICCs) on discharge as they could receive isavuconazole via EFT. These patients were continued on isavuconazole via EFT for a median of 17 days (range 6–60) at the time of data analysis. The total medication cost avoidance for these patients was 173 doses or $27 041.63.

Discussion

To our knowledge, this is the largest case series of patients receiving isavuconazole via EFT for prevention or treatment of IFI with concomitant TDM. The median and range of blood concentrations achieved in our patient population are similar to previously reported pharmacokinetic data from patients receiving IV and capsules swallowed whole by mouth in clinical trial and real-world settings.^5,8,9

Currently, there is no defined exposure–response relationship for isavuconazole efficacy or safety, unlike other triazoles.¹⁰ In clinical trials, isavuconazole-treated patients achieved a median level of 2.48 μg/mL (range 0.19–5.63) on Day 7 of therapy.¹⁰ When 283 real-world isavuconazole samples were compared with samples from patients with TDM from clinical trials, approximately 90% of both populations achieved concentrations ≥1 μg/mL, the putative threshold concentration for treatment effect.¹¹ Indeed, 89% of our study population achieved this threshold, suggesting no difference in EFT administration compared with IV or traditional oral administration. Additionally, six patients had nearly identical IV and EFT isavuconazole concentrations, suggesting the bioavailability of opened, sprinkled isavuconazonium sulphate powder approaches 100% and is similar to that of capsules swallowed whole in this dataset. Nursing administration of isavuconazole was not standardized in our study and the termination of the EFT varied throughout our cohort, strengthening the real-world application of our results. It is important to note there are limited data available on the safety of human exposure to isavuconazonium sulphate powder and the compound is hygroscopic, so contents should be rapidly administered once opened to prevent degradation or dissolution.

One patient in our study had breakthrough IFI on isavuconazole prophylaxis (UPMC-1) despite a level of 1.9 μg/mL. This is consistent with a number of reports highlighting that breakthrough IFI while on prophylaxis or treatment with isavuconazole may occur in a small subset of patients.^12–14 One patient experienced isavuconazole-related nausea (UPMC-3, level 1.1 μg/mL) and one patient had treatment failure (UW-2, level 2.9 μg/mL). It has been previously documented that treatment failure can occur irrespective of blood concentration and the observed level of 1.1 μg/mL was incongruent with the associated adverse event as emerging data suggest a toxicity threshold of 5.13 μg/mL, particularly for gastrointestinal (GI) side effects.¹⁵ One patient in our study (UPMC-11) had a trough of 5.2 μg/mL; no isavuconazole-related adverse events were reported.

Due to the dose-proportional pharmacokinetics, modest interpatient variability and lack of toxicity or efficacy threshold, routine TDM may not be warranted in patients receiving isavuconazole.¹¹ However, TDM is reasonable to consider in patients with deranged or unpredictable pharmacokinetics (e.g. children¹⁶ and the critically ill), reduced absorption, drug–drug interactions (e.g. CYP inducers) or infected with non-WT pathogens (i.e. elevated MIC). It is known that certain patients may require increased isavuconazole dosages such as those on extracorporeal membrane oxygenation, but not those receiving renal replacement therapy or with mucositis.^17–19 Based on the results of our study, administration of isavuconazole capsules via EFT is an option for patients unable to take capsules orally; however, we recommend TDM for all patients receiving isavuconazole via EFT to ensure absorption.

The benefits of enteral therapy over IV therapy are substantial. Our study demonstrated drug cost savings and the ability to avoid PICC line placement at discharge in patients with EFT requiring isavuconazole. While only EFT administration was assessed in our study, it may be reasonable to open and sprinkle the contents of isavuconazonium sulphate capsules on food for patients with oropharyngeal disorders who are unable to swallow pills or tablets.

Conclusions

Nineteen transplant recipients received opened, sprinkled isavuconazonium sulphate capsules via EFT for prevention or treatment of IFI, with concomitant TDM. Results from this cohort are consistent with published clinical trial and real-world TDM data for patients receiving IV or traditional oral capsule administration. It is reasonable to consider opening isavuconazonium sulphate capsules and administering the contents enterally for prevention and treatment of IFI.