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Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy
- Source :
- Antimicrob Agents Chemother
- Publication Year :
- 2020
-
Abstract
- Aspergillus galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. The pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of Aspergillus fumigatus IPA at doses between 2 and 20 mg/kg per day. Sparse plasma sampling was used to obtain PK data at steady state, and the serum galactomannan index (GMI), as a dynamic endpoint of antifungal response, was obtained every other day, in addition to conventional outcome parameters including survival and fungal tissue burden. Nonparametric PK/PD model building was performed using the Pmetrics package in R. A one-compartment model with linear elimination best described the PK of posaconazole. The PD effect of posaconazole exposure in plasma on the GMI in serum was best described by dynamic Hill functions reflecting growth and killing of the fungus. Through calculations of the area under the concentration-time curve from 0 to 24 h (AUC(0–24)) at steady state, the exposure-response relationship between posaconazole and the GMI for treatment followed a sigmoidal function with an asymptote forming above an AUC(0–24) of 30 mg · h/liter. All prophylactic doses were able to control the fungal burden. A nonparametric population PK/PD model adequately described the effect of posaconazole in prophylaxis and treatment of experimental IPA. An AUC(0–24) greater than 30 mg · h/liter was associated with adequate resolution of the GMI, which well supports previously suggested exposure-response relationships in humans.
- Subjects :
- Posaconazole
Antifungal Agents
Population
Microbial Sensitivity Tests
Pharmacology
Clinical Therapeutics
Aspergillosis
030226 pharmacology & pharmacy
Aspergillus fumigatus
Mannans
03 medical and health sciences
Galactomannan
chemistry.chemical_compound
0302 clinical medicine
Pharmacokinetics
Medicine
Animals
Humans
Pharmacology (medical)
education
Invasive Pulmonary Aspergillosis
0303 health sciences
education.field_of_study
biology
030306 microbiology
business.industry
Galactose
Liter
Triazoles
medicine.disease
biology.organism_classification
Disease Models, Animal
Infectious Diseases
chemistry
Pharmacodynamics
Rabbits
business
medicine.drug
Subjects
Details
- ISSN :
- 10986596
- Volume :
- 65
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Antimicrobial agents and chemotherapy
- Accession number :
- edsair.doi.dedup.....bf754144b06050c5fb96a3c969c26afa