Pharmacokinetic/pharmacodynamic integration of amphenmulin: a novel pleuromutilin derivative against.

Abstract

Amphenmulin is a novel pleuromutilin derivative with great anti-mycoplasma potential. The present study evaluated the action characteristics of amphenmulin againstusing pharmacokinetic/pharmacodynamic (PK/PD) modeling approaches. Following intravenous administration, amphenmulin exhibited an elimination half-life of 2.13 h and an apparent volume of distribution of 3.64 L/kg in healthy broiler chickens, demonstrating PK profiles of extensive distribution and rapid elimination. The minimum inhibitory concentration (MIC) of amphenmulin againstwas determined to be 0.0039 µg/mL using the broth microdilution method, and the analysis of the static time-kill curves through the sigmoidmodel showed a highly correlated relationship (R ≥ 0.9649) between the kill rate and drug concentrations (1-64 MIC). A one-compartment open model with first-order elimination was implemented to simulate theanti-mycoplasma effect of amphenmulin, and it was found that bactericidal levels were reached with continuous administration for 3 days at doses exceeding 0.8 µg/mL. Furthermore, the area under the concentration-time curve divided by MIC (AUC/MIC) correlated well with the anti-mycoplasma effect of amphenmulin within 24 h after each administration, with a target value of 904.05 h for predicting a reduction ofby 1 LogCFU/mL. These investigations broadened the antibacterial spectrum of amphenmulin and revealed its characteristics of action against, providing a theoretical basis for further clinical development.IMPORTANCEhas long been recognized as a significant pathogen causing global livestock production losses and public health concerns, and the use of antimicrobial agents is currently one of the mainstream strategies for its prevention and control. Amphenmulin is a promising candidate pleuromutilin derivative that was designed, synthesized, and screened by our laboratory in previous studies. Moreover, this study further confirms the excellent antibacterial activity of amphenmulin againstand reveals its action characteristics and model targets onby establishing anpharmacokinetic/pharmacodynamic synchronization model. These findings can further broaden the pharmacological theoretical basis of amphenmulin and serve as data support for its clinical development, which is of great significance for the discovery of new antimicrobial drugs and the control of bacterial diseases in humans and animals.