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Updated: Mar 22, 2026
Histological Quantification to Determine Lung Fungal Burden in Experimental Aspergillosis
Published on: March 9, 2018
Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical
Laura L Kovanda1, Ruta Petraitiene2, Vidmantas Petraitis2
1Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK Astellas Pharma Global Development, Inc., Northbrook, IL, USA.
Objectives:
Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored.
Methods:
The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations.
Results:
Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ± 1.8, which is a 50% reduction from the starting GMI in the experiment.
Conclusions:
The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.
Insights
This study explored the relationship between isavuconazole exposure and fungal infection clearance in rabbits. The findings support using this model to develop new antifungal treatments.
Area of Science:
- Pharmacology
- Mycology
- Infectious Diseases
Background:
- Isavuconazole is a broad-spectrum triazole antifungal agent.
- Invasive pulmonary aspergillosis is a serious fungal infection.
- Understanding exposure-response relationships is crucial for optimizing antifungal therapy.
Purpose of the Study:
- To explore the exposure-response relationship of isavuconazole in experimental invasive pulmonary aspergillosis.
- To use galactomannan index (GMI) suppression as a marker for disease clearance.
- To bridge findings from a rabbit model to human pharmacokinetic data.
Main Methods:
- Mathematical modeling was used to link isavuconazole exposure to GMI suppression in neutropenic rabbits.
- Pharmacokinetic (PK) data from a human clinical trial were used for Monte Carlo simulations.
- A population PK/pharmacodynamic (PD) target was established and validated in the rabbit model.
Main Results:
- A mean isavuconazole AUC/MIC of 79.65 produced half-maximal GMI suppression (EC50).
- Near-maximal GMI suppression (EC80) was achieved at an AUC/MIC of approximately 130.
- The established PK/PD target predicted a 50% reduction in GMI in the rabbit model, aligning with clinical trial outcomes.
Conclusions:
- The study validates the rabbit model and GMI suppression endpoint for evaluating isavuconazole.
- The findings support the PK-PD endpoint and have implications for antifungal interpretive breakpoints.
- This model serves as a valuable tool for the development of novel antifungal agents.
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