Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

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...

Full description

Saved in:
Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2017-12, Vol.61 (12)
Main Authors: Desai, Amit V, Kovanda, Laura L, Hope, William W, Andes, David, Mouton, Johan W, Kowalski, Donna L, Townsend, Robert W, Mujais, Salim, Bonate, Peter L
Format: Article
Language:English
Subjects:
Alanine Transaminase - blood
Antifungal Agents
Antifungal Agents - pharmacokinetics
Antifungal Agents - therapeutic use
Aspartate Aminotransferases - blood
Aspergillosis
Aspergillosis - drug therapy
Clinical Therapeutics
Dose-Response Relationship, Drug
Drug Monitoring
Humans
Invasive Fungal Infections
Invasive Fungal Infections - drug therapy
Nitriles
Nitriles - pharmacokinetics
Nitriles - therapeutic use
Pyridines
Pyridines - pharmacokinetics
Pyridines - therapeutic use
Triazoles
Triazoles - pharmacokinetics
Triazoles - therapeutic use
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the 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 populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship ( > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.01034-17