In vivo PK/PD integration of p-furoylamphenmulin against Mycoplasma pneumoniae and its anti-inflammatory efficacy.
Mycoplasma pneumoniae is the primary pathogen of community-acquired bacterial pneumonia in humans. Children and adolescents are particularly susceptible, and a dry cough is the most common clinical symptom. In severe cases, this may progress to acute respiratory distress syndrome. To determine the anti-M. pneumoniae and anti-inflammatory activities of a novel pleuromutilin derivative, 22-(4-((2-furan-1-yl)acetamido)phenyl)thio) deoxypleuromutilin (p-furoylamphenmulin, or PFAPM).
We utilized M. pneumoniae-infected mice to conduct in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies. The recommended dose was calculated based on PK/PD analysis, and treatment trials were performed at this dose to validate the fitted outcomes and investigate the anti-inflammatory effects.
The PK/PD results indicated that PFAPM exhibited an absorption half-life (T1/2ka) of 0.07 h and an elimination half-life (T1/2kel) of 0.87 h, with corresponding AUC values ranging from 1.18 to 8.33 μg·h/mL at doses of 10-80 mg/kg. When the mycoplasma load decreased by 3 log10 cfu/mL, the corresponding AUC48h/MIC and Cmax/MIC values were 7617.62 h and 1256.76, respectively, at a dose of 67.66 mg/kg. ELISA and flow cytometry analysis revealed that drug treatment significantly reduced cytokines and inflammatory cells associated with T helper 1 (Th1) and T helper 2 (Th2) immune responses.
AUC48h/MIC was the best parameter to describe the PK/PD relationship. The bactericidal effect was achieved at a dose of 67.66 (∼68) mg/kg. Pleuromutilins can reduce Th1 and Th2 inflammation.
We utilized M. pneumoniae-infected mice to conduct in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies. The recommended dose was calculated based on PK/PD analysis, and treatment trials were performed at this dose to validate the fitted outcomes and investigate the anti-inflammatory effects.
The PK/PD results indicated that PFAPM exhibited an absorption half-life (T1/2ka) of 0.07 h and an elimination half-life (T1/2kel) of 0.87 h, with corresponding AUC values ranging from 1.18 to 8.33 μg·h/mL at doses of 10-80 mg/kg. When the mycoplasma load decreased by 3 log10 cfu/mL, the corresponding AUC48h/MIC and Cmax/MIC values were 7617.62 h and 1256.76, respectively, at a dose of 67.66 mg/kg. ELISA and flow cytometry analysis revealed that drug treatment significantly reduced cytokines and inflammatory cells associated with T helper 1 (Th1) and T helper 2 (Th2) immune responses.
AUC48h/MIC was the best parameter to describe the PK/PD relationship. The bactericidal effect was achieved at a dose of 67.66 (∼68) mg/kg. Pleuromutilins can reduce Th1 and Th2 inflammation.
Authors
Xia Xia, Zhou Zhou, Chen Chen, Liang Liang, Deng Deng, Bai Bai, Tang Tang, Ding Ding
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