ABSTRACT
Conventional itraconazole (C-ITZ) suffers from absorption variability. SUBA-itraconazole (S-ITZ) is more bioavailable than C-ITZ at steady state in a fed condition, but there are no data comparing the two under a fasted state. An open-label, single-dose, randomized, bioequivalence study was performed comparing S-ITZ to C-ITZ capsules under fasted and fed conditions in healthy adults measuring itraconazole and hydroxyitraconazole plasma levels. This study demonstrated less variability of S-ITZ compared to C-ITZ capsules under fasted conditions.
KEYWORDS: itraconazole, endemic mycoses, bioavailability, pharmacokinetics
TEXT
Itraconazole (ITZ) is a broad-spectrum triazole with antifungal activity against many medically important fungi (1–5). Conventional itraconazole (C-ITZ) is available as a capsule and in oral solution, which have unreliable absorption resulting in variable pharmacokinetics (PK) (5, 6). The effect of food on C-ITZ absorption is subject to interpatient variability up to 15-fold (7). As a result, unpredictable supertherapeutic or subtherapeutic plasma levels of ITZ and its major active metabolite hydroxyitraconazole (OH-ITZ) are occasionally experienced. To overcome these limitations, a novel formulation of ITZ labeled SUper BioAvailable (SUBA)-itraconazole (S-ITZ) was developed. S-ITZ has a relative bioavailability of 180% compared to C-ITZ and an absolute bioavailability up to 90%. The 65-mg capsule S-ITZ formulation achieves bioequivalence to a 100-mg capsule of C-ITZ with fewer adverse events (AEs) (8, 9). There are no data comparing these formulations in fed and fasted states.
This was an open-label, single-dose, randomized, four-period, four-treatment, four-sequence, crossover bioequivalence study evaluating the relative bioavailability of a single oral dose of S-ITZ compared to C-ITZ capsules when administered under fasted and fed conditions. Participants were healthy, aged 18 to 65 years, male or female, nonsmokers, with body mass indices of 18 to 30, and without drug allergies who gave informed consent. Full inclusion and exclusion criteria are listed in Table S1 in the supplemental material. Subjects in a fasted or fed state received S-ITZ 65-mg (10) or C-ITZ 100-mg (11) capsules in each study period (A, B, C, and D) in accordance with the randomization schedule summarized in Table 1. The crossover study design allowed comparison of PK parameters within the same subject. No blinding of doses was performed. Blood samples were collected 60 min prior to dosing and prior to breakfast for subjects following the fed regimen and between 1 and 120 h postdose administration. ITZ and OH-ITZ plasma levels were measured by liquid chromatography with tandem mass spectrometry. The area under the plasma concentration over the dosing interval (AUCt), the area under the plasma concentration extrapolated to infinity (AUCinf), observed maximum plasma concentration (Cmax), the time to Cmax (Tmax), the elimination rate constant (kel), and the half-life (t1/2) were estimated based on plasma measurements.
TABLE 1.
Treatment received according to study period and randomization schedulea
Study period | Treatment received | |||
---|---|---|---|---|
A | S-ITZ 65 mg × 1 dose under fasted conditions | |||
B | S-ITZ 65 mg × 1 dose under fed conditions | |||
C | C-ITZ 100 mg × 1 dose under fasted conditions | |||
D | C-ITZ 100 mg × 1 dose under fed conditions | |||
Randomization schedule |
||||
Sequence | Treatment period 1 | Treatment period 2 | Treatment period 3 | Treatment period 4 |
1 | A | D | B | C |
2 | B | A | C | D |
3 | C | B | D | A |
4 | D | C | A | B |
S-ITZ, SUBA-itraconazole; C-ITZ, conventional itraconazole. Subjects under fasted conditions (A and C) received their dose following an overnight fast of at least 10 h; subjects under fed conditions (B and D) received their dose within 30 min of consuming a high-fat, high-calorie meal (total protein calories, 150; carbohydrate calories, 250; and fat calories, 500), preceded by an overnight fast of at least 10 h. After dosing, all subjects fasted for at least 4 h in all periods. The interval between doses in each study period was at least 14 days. Subjects swallowed one whole capsule with 240 ml of ambient temperature water, and any other fluids (except for milk given with the meal) were restricted from 1 h predosing until 1 h postdose. Caffeine-containing foods and beverages were not allowed within 72 h prior to the dose in each period and throughout the times of blood sample collection. Grapefruit was not allowed for 7 days prior to the first dosing occasion and until after completion of the study.
Descriptive statistics for ITZ and OH-ITZ were performed on plasma concentrations and the estimated PK parameters by treatments. The statistical information provided for AUCt, AUCinf, and Cmax were geometric means, arithmetic means, ratios of means, and 90% confidence intervals (CI) with log transformation provided for measures used to demonstrate bioequivalence. Analysis of variance (ANOVA) was performed on log-transformed AUCt, AUCinf, and Cmax. The absence of food effect was established if the 90% confidence interval of the geometric mean ratio of the fed/fasting state for ITZ AUCt, AUCinf, and Cmax are contained within the 80 to 125% U.S. Food and Drug Administration (FDA) acceptance limits. The treatment differences in Tmax were analyzed nonparametrically and separately for each pair of contrasts via the Hodges-Lehmann estimator. The point estimate of the Hodges-Lehmann’s median difference and the lower and upper limits of the exact 100 × (1 – α)% confidence interval for the above median difference were obtained based on the Wilcoxon signed-rank distribution. An asymptotic confidence interval was also computed by applying the normal approximation to the Wilcoxon signed-rank distribution.
Intersubject variability for log-transformed AUCt, AUCinf, and Cmax was assessed using homogeneity of variance. The variances of the untransformed and log-transformed AUCt, AUCinf, and Cmax parameters were compared between treatment for study periods A and C (fasted) and between treatment for study periods B and D (fed) graphically using boxplots (see Fig. S1 to S12 in the supplemental material). The differences in variances between log-transformed S-ITZ and C-ITZ were assessed with Bartlett’s or Brown-Forsythe’s test as appropriate. The Statistical Analysis System (SAS v9.2) was used for all statistical computations.
Fifty-two healthy volunteers were initially enrolled. The mean age of the study population analyzed was 39 years (range, 19 to 54 years) composed of 51.9% female and 48.1% males. Most subjects were white (50%), followed by Asian (28.8%) and African-American (21.2%). Fifty volunteers completed the study; two subjects were excluded due to a protocol violation given failure to finish entire high-fat meal and noncompliance with study drug. Subjects with an estimation of the Cmax and AUC in at least one test period were included in analysis. The study medications were well tolerated under fasted and fed conditions (see Tables S2 to S5).
Under the fasted condition, the AUCinf and Cmax ITZ levels for S-ITZ were higher than those for C-ITZ (23 and 62%, respectively). Under fed conditions, S-ITZ exhibited a 5% lower AUCinf and a 20% lower Cmax compared to C-ITZ. Similar results were observed for OH-ITZ levels and are available in Table 2. There was no Tmax difference between formulations under fasted conditions; under fed conditions, the median Tmax for S-ITZ was 2.5 h longer compared to C-ITZ (Table 2). The geometric mean S-ITZ/C-ITZ ratios for ITZ levels under fasted conditions were 122.76% (90% CI = 109.72 to 137.34%) and 161.75% (90% CI = 141.40 to 185.02%) for AUCinf and Cmax, respectively (Table 3). Under fed conditions, the geometric mean S-ITZ/C-ITZ ratios for ITZ were 94.67% (90% CI = 85.35 to 105.01%) and 80.26% (90% CI = 67.61 to 95.27%) for the AUCinf and Cmax, respectively (Table 3). The geometric mean S-ITZ/C-ITZ ratios for OH-ITZ under fasted conditions were 125.77% (90% CI = 111.40 to 141.99%) and 143.40% (90% CI = 128.19 to 160.42%) for the AUCinf and Cmax, respectively. Under fed conditions, the geometric mean S-ITZ/C-ITZ ratios were 91.86% (90% CI = 79.26 to 106.47%) and 84.25% (90% CI = 73.09 to 97.11%) for the AUCinf and Cmax, respectively (Table 3).
TABLE 2.
Pharmacokinetic results of itraconazole and hydroxyitraconazole levels comparing SUBA-itraconazole and conventional itraconazole under fasted and fed statesa
Parameter | Itraconazole |
Hydroxyitraconazole |
||||||
---|---|---|---|---|---|---|---|---|
S-ITZ: fasted (65 mg ITZ) | S-ITZ: fed (65 mg ITZ) | C-ITZ: fasted (100 mg ITZ) | C-ITZ: fed (100 mg ITZ) | S-ITZ: fasted (65 mg ITZ) | S-ITZ: fed (65 mg ITZ) | C-ITZ: fasted (100 mg ITZ) | C-ITZ: fed (100 mg ITZ) | |
n = 51 | n = 50 | n = 52 | n = 51 | n = 51 | n = 50 | n = 52 | n = 51 | |
Median Tmax in h (range) | 2.50 (1.50–5.00) | 7.50 (4.50–24) | 3.00 (1.50–4.52) | 5.00 (2.50–11.00) | 3.50 (2.00–6.00) | 9.00 (4.50–24) | 4.00 (1.50–5.50) | 5.50 (2.50–12.00) |
Cmax (ng/ml) | 111.910 (44) | 50.299 (50) | 74.362 (57) | 62.224 (55) | 180.514 (31) | 85.902 (36) | 133.969 (46) | 100.818 (41) |
n = 51 | n = 48 | n = 52 | n = 51 | n = 51 | n = 48 | n = 52 | n = 51 | |
AUCinf (ng · h/ml) | 1,006.534 (45) | 684.773 (46) | 879.762 (57) | 754.350 (58) | 1,934.418 (48) | 1,186.126 (50) | 1,656.887 (60) | 1,301.073 (59) |
Thalf (h) | 31.45 (23) | 32.48 (26) | 29.95 (22) | 34.02 (30) | 8.90 (47) | 7.77 (38) | 12.43 (45) | 8.52 (44) |
S-ITZ, SUBA-itraconazole; C-ITZ, conventional itraconazole; ITZ, itraconazole; Cmax, maximum concentration; AUCt, area under the plasma concentration over the dosing interval; AUCinf, area under the curve extrapolated to infinity; kel, elimination rate constant; Thalf, half-life. Cmax, AUCt, AUCinf, kel, and Thalf are expressed as the arithmetic mean (CV%).
TABLE 3.
Contrasts in pharmacokinetic itraconazole and hydroxyitraconazole plasma levels comparing SUBA-itraconazole and conventional itraconazole under fasted and fed statesa
Parameter | Contrast in Cmax (ng/ml) |
Contrast in AUCinf (ng · h/ml) |
||||
---|---|---|---|---|---|---|
RGM (%) | 90% CI | IS CV (%) | RGM (%) | 90% CI | IS CV (%) | |
Itraconazole | ||||||
S-ITZ fasted vs C-ITZ fasted | 161.75 | 141.40–185.02 | 42 | 122.76 | 109.72–137.34 | 35 |
S-ITZ fed vs C-ITZ fed | 80.26 | 67.61–95.27 | 55 | 94.67 | 85.35–105.01 | 32 |
S-ITZ fed vs S-ITZ fasted | 42.87 | 36.61–50.20 | 50 | 69.42 | 63.76–75.58 | 26 |
C-ITZ fed vs C-ITZ fasted | 86.40 | 74.38–100.37 | 48 | 90.01 | 79.34–102.11 | 40 |
S-ITZ fasted vs C-ITZ fed | 187.20 | 164.23–213.40 | 41 | 136.38 | 122.81–151.46 | 33 |
Hydroxyitraconazole | ||||||
S-ITZ fasted vs C-ITZ fasted | 143.40 | 128.19–160.42 | 35 | 125.77 | 111.40–141.99 | 38 |
S-ITZ fed vs C-ITZ fed | 84.25 | 73.09–97.11 | 45 | 91.86 | 79.26–106.47 | 46 |
S-ITZ fed vs S-ITZ fasted | 45.66 | 40.06–52.04 | 41 | 60.00 | 52.65–68.37 | 40 |
C-ITZ fed vs C-ITZ fasted | 77.72 | 68.60–88.05 | 39 | 82.14 | 71.48–94.40 | 44 |
S-ITZ fasted vs C-ITZ fed | 184.51 | 166.39–204.60 | 32 | 153.11 | 136.49–171.76 | 36 |
S-ITZ, SUBA-itraconazole; C-ITZ, conventional itraconazole; Cmax, maximum concentration; CI, confidence interval; RGM, ratio of geometric means; IS CV, intrasubject coefficient of variation; AUCinf, area under the curve extrapolated to infinity.
Decreased relative bioavailability in the presence of food was seen for S-ITZ and C-ITZ. The mean AUCinf and Cmax for both ITZ and OH-ITZ were lower (31 and 40% for AUCinf; 57 and 54% for Cmax) when S-ITZ was administered after the study meal; a similar decrease was seen in C-ITZ (10 and 18% for AUCinf; 14 and 22% for Cmax) for ITZ and OH-ITZ, respectively (Table 3).
Regarding intersubject variability, treatment C (C-ITZ under fasting conditions) for both AUC and Cmax ITZ parameters, exhibited the largest variability (0.422 and 0.372 variances, respectively). While treatment for study period B (S-ITZ under fed conditions) exhibited the lowest intersubject (0.179 and 0.187, respectively). These observed differences did not reach statistical significance. Similarly, the largest intersubject variability of OH-ITZ was exhibited by treatment for study period C for AUCt, AUCinf, and Cmax (0.456, 0.439, and 0.246, respectively). The lowest values for the intersubject variance within each parameter were exhibited by treatment B: 0.214, 0.218, and 0.129, respectively. The only parameter that reached statistical significance (P = 0.0028) under fasting conditions was the difference between the variability of the Cmax.
This study adds to the growing body of evidence that S-ITZ achieves bioequivalence to C-ITZ in terms of the extent of exposure for both ITZ and OH-ITZ, as measured by AUCt and AUCinf (12–14). In the fasting state, S-ITZ exhibited 23% larger AUCt and AUCinf values with geometric means within the wider bioequivalence range. In the fed state compared to C-ITZ capsules, S-ITZ had a 10% lower AUCt and a 5% lower AUCinf, which is within the wider bioequivalence range as defined by the FDA (15). This continued affirmation of the bioequivalence of clinically important PK parameters between S-ITZ and C-ITZ allows clinicians to optimize therapeutic choice based upon more patient-centered parameters—less restrictive administration conditions, lower interpatient variability, and subjective drug tolerability.
In this study, administration in a fed state decreased bioavailability of C-ITZ capsule formulation. This runs counter to historical literature of improved bioavailability in the fed state compared to a fasted state (7, 16–19), though it is consistent with more recent data (12, 13). We posit this discrepancy reflects the difficulty clinicians have understanding the complicated PK of C-ITZ. Although supertherapeutic levels have increased adverse events, subtherapeutic levels are associated with poor clinical outcomes (20, 23, 25, 26). To ameliorate the issues with capsule administration, a C-ITZ oral solution was developed, although many patients do not tolerate it due to the unpalatable taste and poor gastrointestinal tolerability (21, 22).
More recently, S-ITZ was designed to improve bioavailability and received FDA approval in 2018 (10). The success of this development goal is evidenced by plasma trough levels minimally affected by fasted or fed conditions and enhanced absorption in the presence of acid suppression (13). Prior data comparing S-ITZ to C-ITZ capsule formulation demonstrated the relative bioavailability of S-ITZ was 173%, with 21% less interpatient variability (12). Our study had similar findings of greater bioavailability of S-ITZ compared to C-ITZ given the bioequivalence at a lower dose of 65 mg versus 100 mg. The interpatient variability in our study was lower in the S-ITZ than the C-ITZ, although it did not reach statistical significance but continued to demonstrate a trend of decreased intersubject variability (12, 14). An additional study identified a trend toward treatment failure in the C-ITZ solution group; S-ITZ had 7.4% treatment failure compared to 23.3% for the C-ITZ solution, though it did not reach statistical significance (P = 0.096) (23).
S-ITZ has performed favorably throughout early trials and recent direct comparison studies to other ITZ formulations. The growing body of literature on the PK of S-ITZ suggest improved relative bioavailability and less restrictive administration conditions (12, 13, 18). The lone comparison trial in an at-risk patient population showed faster time to therapeutic levels and fewer patients with subtherapeutic levels (23). Promising data continue to accumulate while awaiting the results of MSG15, a trial comparing S-ITZ to C-ITZ for the treatment of endemic mycoses (23).
ACKNOWLEDGMENTS
This study was funded by Mayne Pharma.
A.S. received grant support from Astellas and consulting fees from Mayne, Scynexis, Viamet, Astellas, and Minnetronix. P.L., S.M., and B.B. are employed by Mayne.
Footnotes
Supplemental material is available online only.
REFERENCES
- 1.Chapman SW, Dismukes WE, Proia LA, Bradsher RW, Pappas PG, Threlkeld MG, Kauffman CA, Infectious Diseases Society of America. 2008. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis 46:1801–1812. doi: 10.1086/588300. [DOI] [PubMed] [Google Scholar]
- 2.Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA, Infectious Diseases Society of America. 2007. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 45:807–825. doi: 10.1086/521259. [DOI] [PubMed] [Google Scholar]
- 3.Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Geertsma F, Hoover SE, Johnson RH, Kusne S, Lisse J, MacDonald JD, Meyerson SL, Raksin PB, Siever J, Stevens DA, Sunenshine R, Theodore N. 2016. Infectious Diseases Society of America (IDSA) clinical practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis 63:e112-146–e146. doi: 10.1093/cid/ciw360. [DOI] [PubMed] [Google Scholar]
- 4.Galgiani JN, Catanzaro A, Cloud GA, Johnson RH, Williams PL, Mirels LF, Nassar F, Lutz JE, Stevens DA, Sharkey PK, Singh VR, Larsen RA, Delgado KL, Flanigan C, Rinaldi MG. 2000. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Ann Intern Med 133:676–686. doi: 10.7326/0003-4819-133-9-200011070-00009. [DOI] [PubMed] [Google Scholar]
- 5.Nett JE, Andes DR. 2016. Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am 30:51–83. doi: 10.1016/j.idc.2015.10.012. [DOI] [PubMed] [Google Scholar]
- 6.Ashley ESD, Lewis R, Lewis JS, Martin C, Andes D. 2006. Pharmacology of systemic antifungal agents. Clinical Infectious Diseases 43:S28–S39. doi: 10.1086/504492. [DOI] [Google Scholar]
- 7.Poirier JM, Berlioz F, Isnard F, Cheymol G. 1996. Marked intra- and inter-patient variability of itraconazole steady state plasma concentrations. Therapie 51:163–167. [PubMed] [Google Scholar]
- 8.Mangalore RP, Moso MA, Cronin K, Young K, McMahon JH. 2018. Treatment of disseminated histoplasmosis in advanced HIV using itraconazole with increased bioavailability. Int J STD AIDS 29:1448–1450. doi: 10.1177/0956462418788129. [DOI] [PubMed] [Google Scholar]
- 9.Thompson GR, III, Lewis P, Mudge S, Patterson TF, Burnett BP. 2020. Open-label crossover oral bioequivalence PK comparison for a 3-day loading dose regimen and 15-day steady-state administration of SUBA™-itraconazole and conventional itraconazole capsules in healthy adults. Antimicrob Agents Chemother 64:e00400-20. doi: 10.1128/AAC.00400-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Mayne Pharma Inc. 2019. TOLSURA®: itraconazole capsules. Approved 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=306352d1-9d5a-49ad-b72d-893b99546861. Accessed June 2020.
- 11.Janssen Pharmaceuticals, Inc. 2020. SPORANOX®: itraconazole capsules. Approved 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0. Accessed June 2020.
- 12.Abuhelwa AY, Foster DJ, Mudge S, Hayes D, Upton RN. 2015. Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and Sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob Agents Chemother 59:5681–5696. doi: 10.1128/AAC.00973-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Lindsay J, Mudge S, Thompson GR, III.. 2018. Effects of food and omeprazole on a novel formulation of super bioavailability itraconazole in healthy subjects. Antimicrob Agents Chemother 62:e01723-18. doi: 10.1128/AAC.01723-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Thompson GR, III, Lewis P, Mudge S, Patterson TF, Burnett BP. 2020. Open-label crossover oral bioequivalence pharmacokinetics comparison for a 3-day loading dose regimen and 15-day steady-state administration of SUBA-itraconazole and conventional itraconazole capsules in healthy adults. Antimicrob Agents Chemother 64:e00400-20. doi: 10.1128/AAC.00400-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Haidar SH, Davit B, Chen M-L, Conner D, Lee L, Li QH, Lionberger R, Makhlouf F, Patel D, Schuirmann DJ, Yu LX. 2008. Bioequivalence approaches for highly variable drugs and drug products. Pharm Res 25:237–241. doi: 10.1007/s11095-007-9434-x. [DOI] [PubMed] [Google Scholar]
- 16.Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V. 1993. Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers. Antimicrob Agents Chemother 37:778–784. doi: 10.1128/aac.37.4.778. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Lestner J, Hope WW. 2013. Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol 9:911–926. doi: 10.1517/17425255.2013.794785. [DOI] [PubMed] [Google Scholar]
- 18.Van Peer A, Woestenborghs R, Heykants J, Gasparini R, Gauwenbergh G. 1989. The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol 36:423–426. doi: 10.1007/BF00558308. [DOI] [PubMed] [Google Scholar]
- 19.Yun H-y, Baek MS, Park IS, Choi BK, Kwon K-i. 2006. Comparative analysis of the effects of rice and bread meals on bioavailability of itraconazole using NONMEM in healthy volunteers. Eur J Clin Pharmacol 62:1033–1039. doi: 10.1007/s00228-006-0200-5. [DOI] [PubMed] [Google Scholar]
- 20.Wheat J, Hafner R, Korzun AH, Limj MT, Spencer P, Larsen RA, Hecht FM, Powderly W, AIDS Clinical Trial Group. 1995. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Med 98:336–342. doi: 10.1016/S0002-9343(99)80311-8. [DOI] [PubMed] [Google Scholar]
- 21.Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. 2014. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 69:1162–1176. doi: 10.1093/jac/dkt508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Marks DI, Pagliuca A, Kibbler CC, Glasmacher A, Heussel C‐P, Kantecki M, Miller PJS, Ribaud P, Schlamm HT, Solano C, Cook G, for the IMPROVIT Study Group. 2011. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation. Br J Haematol 155:318–327. doi: 10.1111/j.1365-2141.2011.08838.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Lindsay J, Sandaradura I, Wong K, Arthur C, Stevenson W, Kerridge I, Fay K, Coyle L, Greenwood M. 2017. Serum levels, safety and tolerability of new formulation SUBA-itraconazole prophylaxis in patients with haematological malignancy or undergoing allogeneic stem cell transplantation. J Antimicrob Chemother 72:3414–3419. doi: 10.1093/jac/dkx295. [DOI] [PubMed] [Google Scholar]
- 24.ClinicalTrials.gov. 2020. Endemic mycoses treatment with SUBA-itraconazole versus itraconazole (MSG15). https://clinicaltrials.gov/ct2/show/NCT03572049. Accessed 8 August 2020.
- 25.Sharpe MD, Ghent C, Grant D, Horbay GL, McDougal J, David Colby W. 2003. Efficacy and safety of itraconazole prophylaxis for fungal infections after orthotopic liver transplantation: a prospective, randomized, double-blind study. Transplantation 76:977–983. doi: 10.1097/01.TP.0000085653.11565.52. [DOI] [PubMed] [Google Scholar]
- 26.Grigg AP, Brown M, Roberts AW, Szer J, Slavin MA. 2004. A pilot study of targeted itraconazole prophylaxis in patients with graft-versus-host disease at high risk of invasive mould infections following allogeneic stem cell transplantation. Bone Marrow Transplant 34:447–453. doi: 10.1038/sj.bmt.1704614. [DOI] [PubMed] [Google Scholar]
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