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Clinical Trial
. 2017 Jun;73(6):669-678.
doi: 10.1007/s00228-017-2213-7. Epub 2017 Mar 7.

Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics

Robert W Townsend  1 , Shahzad Akhtar  2 , Harry Alcorn  3 , Jolene K Berg  3 , Donna L Kowalski  2 , Salim Mujais  2 , Amit V Desai  2
Affiliations
Clinical Trial

Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics

Robert W Townsend et al. Eur J Clin Pharmacol. 2017 Jun.

Abstract

Purpose: The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728.

Methods: A single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration (C max), area under the concentration-time curve (AUC) from time of dose to 72 h (AUC72), AUC extrapolated to infinity (AUC∞), AUC to last measurable concentration (AUClast), half-life (t ½ h), volume of distribution (V z), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD.

Results: Isavuconazole C max values were 4% higher in mild RI and 7, 14, and 21% lower in participants with moderate RI, severe RI, or ESRD versus the healthy control group, respectively. When hemodialysis occurred post-dose (day 15), participants with ESRD had a 30% increase in AUC72 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC∞ and AUClast) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t1/2 (day 1) was 125.5 ± 63.6 h (healthy control group), 204.5 ± 82.6 h (ESRD group) in part 1, and 140.5 ± 77.7 h (healthy control group), 117.0 ± 66.2 h (mild RI), 158.5 ± 56.4 h (moderate RI), and 145.8 ± 65.8 L/h (severe RI) in part 2. CL was 2.4 ± 0.8 L/h (healthy control group) and 2.9 ± 1.3 L/h (ESRD group) in part 1 and 2.4 ± 1.2 L/h (healthy control group), 2.5 ± 1.0 L/h (mild RI), 2.2 ± 0.8 L/h (moderate RI), and 2.4 ± 0.8 L/h (severe RI) in part 2. The V z was 382.6 ± 150.6 L in the healthy control group and 735.6 ± 277.3 L in ESRD patients on day 1 in part 1 of the study. In part 2 of the study, V z was 410.8 ± 89.7 L in the healthy control group, 341.6 ± 72.3 L in mild RI, 509.1 ± 262.2 L in moderate RI, and 439.4 L in severe RI.

Conclusions: Based on the findings of this study, dose adjustments of isavuconazole are unlikely to be required in individuals with RI or in those with ESRD who receive hemodialysis.

Keywords: End-stage renal disease; Isavuconazole; Pharmacokinetics; Renal impairment.

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Conflict of interest statement

R.W. Townsend, D.L. Kowalski, S. Mujais, and A.V. Desai are all employees of Astellas Pharma Global Development, Inc. S. Akhtar was an employee of Astellas Pharma Global Development, Inc. at the time of the study. H. Alcorn and J. Berg are employees of DaVita Clinical Research who were contracted by Astellas Pharma Global Development, Inc. to perform this trial. This study was funded by Astellas Pharma Global Development, Inc. Editorial support was provided by John Clarke, Envision Pharma Group, Horsham, UK, funded by Astellas Pharma Global Development, Inc.

Figures

Fig. 1
Fig. 1
Mean (standard deviation [SD]) plasma concentration–time profiles for isavuconazole in a healthy control group (day 1) versus participants with end-stage renal disease on both day 1 and day 15 and b for participants with mild, moderate, and severe RI versus the healthy control group
Fig. 2
Fig. 2
The relationship between total clearance of isavuconazole (CL) and renal function in relation to creatinine clearance (CLcr) by Cockcroft–Gault (CG) method (a) and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) method (b). CI as confidence intervals
See this image and copyright information in PMC

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