Antimicrobial agents and chemotherapy, Dec 18, 2017
Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triaz... more Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and other filamentous fungi from the SECURE trial. Two hundred and thirty one patients who received the clinical dosing regimen and had exposure parameters were included in this analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included: all-cause mortality through Day 42 in the intent-to-treat (ITT) and modified ITT population, data-review committee (DRC)-adjudicated overall respons...
European journal of clinical pharmacology, Jan 7, 2017
The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal d... more 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. 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 ...
Antimicrobial agents and chemotherapy, May 7, 2016
Isavuconazole, administered as prodrug isavuconazonium sulfate, was recently approved by the US F... more Isavuconazole, administered as prodrug isavuconazonium sulfate, was recently approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral data from two hepatic studies and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 L/h (5(th) and 95(th) percentiles: 2.0, 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 L/h (5(th) and 95(th) percentiles: 1.3, 1.8 L/h) and 1.32 L/h (5(th) and 95(th) percentiles...
Antimicrobial agents and chemotherapy, Dec 18, 2017
Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triaz... more Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and other filamentous fungi from the SECURE trial. Two hundred and thirty one patients who received the clinical dosing regimen and had exposure parameters were included in this analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included: all-cause mortality through Day 42 in the intent-to-treat (ITT) and modified ITT population, data-review committee (DRC)-adjudicated overall respons...
European journal of clinical pharmacology, Jan 7, 2017
The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal d... more 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. 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 ...
Antimicrobial agents and chemotherapy, May 7, 2016
Isavuconazole, administered as prodrug isavuconazonium sulfate, was recently approved by the US F... more Isavuconazole, administered as prodrug isavuconazonium sulfate, was recently approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral data from two hepatic studies and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 L/h (5(th) and 95(th) percentiles: 2.0, 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 L/h (5(th) and 95(th) percentiles: 1.3, 1.8 L/h) and 1.32 L/h (5(th) and 95(th) percentiles...
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