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Pharmacokinetics and Pharmacodynamics of Murepavadin in Neutropenic Mouse Models
M J Melchers1,2, J Teague3, P Warn3
1Department of Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Abstract:
Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein-targeting antibiotics. It specifically interacts with LptD and inhibits lipopolysaccharide (LPS) transport. Murepavadin is being developed for the treatment of serious infections by Pseudomonas aeruginosa We determined the plasma protein binding and the pharmacokinetics of murepavadin in plasma and epithelial lining fluid (ELF; pulmonary) in infected animals, and we determined the exposure-response relationship. Treatment of CD-1 neutropenic mice was started 2 h after infection using murepavadin at different dosing frequencies for 24 h, and the number of CFU per lung was determined. The sigmoid maximum-effect model was used to fit the dose-response, and the pharmacodynamic index (PDI) response was used to determine the PDI values, resulting in a static effect and 1-log kill reduction. Using R2 as an indicator of the best fit, the area under the concentration-time curve for the unbound fraction of the drug (fAUC)/MIC ratio correlated best with efficacy. The mean AUC required to provide a static effect was 36.83 mg h/liter (fAUC = 8.25 mg h/liter), and that to provide a 1-log reduction was 44.0 mg h/liter (fAUC = 9.86 mg h/liter). The mean static fAUC/MIC was determined to be 27.78, and that for a 1-log reduction was 39.85. These data may serve to determine doses in humans that are likely to be efficacious.
Insights
Murepavadin, a novel antibiotic targeting outer membrane protein LptD, shows efficacy against Pseudomonas aeruginosa infections. The unbound fraction area under the curve to MIC ratio best predicts its effectiveness in animal models.
Area of Science:
- Pharmacology and Microbiology
- Infectious Diseases
- Drug Development
Background:
- Murepavadin (POL7080) is a novel antibiotic class targeting the outer membrane protein LptD.
- It inhibits lipopolysaccharide (LPS) transport, crucial for Gram-negative bacteria like Pseudomonas aeruginosa.
- Murepavadin is under development for treating serious P. aeruginosa infections.
Purpose of the Study:
- To determine plasma protein binding and pharmacokinetics of murepavadin in infected animal models.
- To establish the exposure-response relationship for murepavadin.
- To identify the pharmacodynamic index (PDI) correlating with efficacy.
Main Methods:
- Pharmacokinetic and protein binding studies in plasma and epithelial lining fluid (ELF) of infected animals.
- Dose-response assessment in CD-1 neutropenic mice infected with P. aeruginosa.
- Sigmoid maximum-effect model and pharmacodynamic index (PDI) analysis to determine efficacy thresholds.
Main Results:
- The ratio of the unbound fraction area under the concentration-time curve (fAUC) to the minimum inhibitory concentration (MIC) best correlated with efficacy (R²).
- Mean fAUC/MIC values for static effect and 1-log reduction were 27.78 and 39.85, respectively.
- Required fAUC for static effect was 8.25 mg·h/L; for 1-log reduction, it was 9.86 mg·h/L.
Conclusions:
- The fAUC/MIC ratio is a key pharmacodynamic index for murepavadin.
- Established exposure-response data can guide the determination of efficacious human doses.
- Murepavadin demonstrates potential as a targeted therapeutic for P. aeruginosa infections.
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