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Randomized Controlled Trial
. 2022 Jun;11(6):744-753.
doi: 10.1002/cpdd.1079. Epub 2022 Feb 21.

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Isavuconazonium Sulfate in Healthy Adult Japanese Subjects

Shinichiro Shirae  1 , Atsushi Ose  1 , Yuji Kumagai  2
Affiliations
Randomized Controlled Trial

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Isavuconazonium Sulfate in Healthy Adult Japanese Subjects

Shinichiro Shirae et al. Clin Pharmacol Drug Dev. 2022 Jun.

Abstract

Isavuconazonium sulfate is the water-soluble prodrug of the novel, broad-spectrum, triazole antifungal agent isavuconazole. This was a first-in-Japanese study assessing the pharmacokinetics, safety, and tolerability of isavuconazonium sulfate. The study was conducted in 2 parts: part 1 (single ascending dose; 100-, 200-, and 400-mg equivalent of isavuconazole oral or intravenous administration); and part 2 (multiple doses for 16 days; 200-mg equivalent of isavuconazole oral or intravenous administration; once-daily administration with a loading regimen every 8 hours for the first 48 hours). A total of 60 and 16 subjects were randomized in part 1 and part 2, respectively. Observed clearance was lower in this study compared to what was previously reported in predominantly White populations and similar to clearance in non-Japanese Asian populations. The range of the plasma isavuconazole concentration in this study was within the range of the pivotal phase 3 study, with no relationship between isavuconazole exposure and either efficacy or safety. There were no serious adverse events, and all reported treatment-emergent adverse events were of mild intensity. This study confirmed that isavuconazonium sulfate was safe and well tolerated in healthy adult Japanese subjects.

Trial registration: ClinicalTrials.gov NCT03471988.

Keywords: isavuconazole; isavuconazonium sulfate; pharmacokinetics; safety; tolerability.

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Conflict of interest statement

S.S. and A.O. are employees of Asahi Kasei Pharma, the sponsor of this study. Y.K. received a consulting fee from Asahi Kasei Pharma.

Figures

Figure 1
Figure 1
Mean plasma isavuconazole concentration–time profile after single administration of isavuconazonium sulfate. (A, B) Mean plasma concentration–time profile after single oral administration of isavuconazonium sulfate at 24 hours (A) and up to 480 hours (B). (C, D) Mean plasma concentration–time profile after single intravenous administration of isavuconazonium sulfate at 24 hours (C) and up to 480 hours (D). PO 100 mg, oral administration of 100‐mg equivalent of isavuconazole; PO 200 mg, oral administration of 200‐mg equivalent of isavuconazole; PO 400 mg, oral administration of 400‐mg equivalent of isavuconazole; IV 100 mg, intravenous administration of 100‐mg equivalent of isavuconazole; IV 200 mg, intravenous administration of 200‐mg equivalent of isavuconazole; IV 400 mg, intravenous administration of 400 mg equivalent of isavuconazole. IV, intravenous; PO, oral.
Figure 2
Figure 2
Mean plasma isavuconazole concentration–time profile after multiple administrations of 200‐mg equivalent of isavuconazole. The inset shows an expanded plot from before dosing to 24 hours on day 16. PO 200 mg, oral administration of 200‐mg equivalent of isavuconazole; IV 200 mg, intravenous administration of 200‐mg equivalent of isavuconazole. IV, intravenous; PO, oral.
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