title: Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Antimicrobial 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.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kovanda
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY, USA.
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY, USA.
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY, USA Departments of Pediatrics and Microbiology & Immunology, Weill Cornell Medicine of Cornell University, New York, NY, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, IL, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Desai
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, IL, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Bonate
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK william.hope@liverpool.ac.uk.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects*; D004195:Disease Models, Animal; D016903:Drug Monitoring; D005260:Female; D005690:Galactose / Q000031:analogs & derivatives; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D008351:Mannans / Q000097:blood; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D009010:Monte Carlo Method; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011817:Rabbits; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D008351:Mannans; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C012990:galactomannan; C508735:isavuconazole; D005690:Galactose