Application of a Physiologically Based Pharmacokinetic Model to Develop a Veterinary Amorphous Enrofloxacin Solid
Kaixiang Zhou1, Meixia Huo1, Wenjin Ma1
1National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan 430070, China.
Pharmaceutics
|April 30, 2021
Summary
This study developed an amorphous enrofloxacin solid dispersion (ENR-SD) granule to improve drug solubility and palatability for treating zoonotic intestinal infections. A PBPK model guided formulation and dosing, suggesting a 10 mg/kg daily dose for efficacy.
Area of Science:
- Veterinary Pharmacology
- Drug Delivery Systems
- Antimicrobial Resistance
Background:
- Zoonotic intestinal pathogens pose significant threats to human and animal health, leading to substantial economic losses in agriculture.
- Enrofloxacin (ENR) is an effective antibiotic, but its clinical use is hindered by poor palatability and low aqueous solubility.
- Developing improved oral formulations of ENR is crucial for effective treatment of intestinal infections.
Purpose of the Study:
- To develop a palatable and highly soluble oral enrofloxacin preparation using an amorphous solid dispersion (ENR-SD) granule.
- To construct a physiologically based pharmacokinetic (PBPK) model for enrofloxacin in pigs to simulate its behavior in intestinal contents.
- To utilize the PBPK model for formulation optimization and dose regimen design against common intestinal pathogens.
Main Methods:
- Preparation of amorphous enrofloxacin solid dispersion (ENR-SD) granules.
- Physicochemical characterization of ENR-SD using DSC and XRD.
- Development and validation of a PBPK model for enrofloxacin in pigs.
- In silico simulation of pharmacokinetics (PK) and parameter sensitivity analysis (PSA).
- Predictive efficacy assessment based on AUC24h/MIC90 ratios.
Main Results:
- ENR-SD granules were successfully prepared, with ENR in an amorphous form and no observed interactions with excipients.
- The PBPK model accurately simulated ENR pharmacokinetics, with PSA identifying the intestinal absorption rate constant (Ka) as a key factor influencing Cmax.
- A 1:5 ratio of ENR to stearic acid yielded high solubility (1190 ± 7.71 µg/mL).
- Predicted AUC24h/MIC90 ratios indicated satisfactory efficacy against Campylobacter jejuni, Salmonella, and Escherichia coli at a dose of 10 mg/kg once daily.
- The PBPK model proved effective for guiding formulation and dose selection.
Conclusions:
- Amorphous solid dispersion technology significantly enhances enrofloxacin solubility and palatability for oral administration.
- The PBPK model is a valuable tool for optimizing drug formulations and predicting effective dose regimens for veterinary applications.
- The developed ENR-SD formulation and proposed 10 mg/kg daily dose show promise for controlling common zoonotic intestinal infections in pigs.
Keywords:
dose designenrofloxacinformulation strategiesintestinal infectionsphysiologically based pharmacokinetics modelsolid dispersionMore Related Videos
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