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

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 (AUC(72)), AUC extrapolated to infinity (AUC(a)), AUC to last measurable concentration (AUC(last)), half-life (t(A 1/2) 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 AUC(72) for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC(a) and AUC(last)) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t(1/2) (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.