Diffusion‐limited PBPK model for predicting pulmonary pharmacokinetics of florfenicol in pig

Abstract

For most bacterial lung infections, the concentration of unbound antimicrobial agent in lung interstitial fluid has been thought to be responsible for antimicrobial efficacy. In this study, a diffusion-limited physiologically based pharmacokinetic (PBPK) model was developed to predict the pulmonary pharmacokinetics of florfenicol (FF) in pigs. The model included separate compartments corresponding to blood, diffusion-limited lung, flow-limited muscle, liver, and kidney and an extra compartment representing the remaining carcass. The absorption rate constant and renal and hepatic clearance of FF were determined in vivo. Other parameters were taken from the literature or optimized based on existing pharmacokinetic data. All mathematical operations during the development of the model were performed using acslXtreme version 3.0.2.1 (Aegis Technologies Group, Inc., Huntsville, AL, USA). The model accurately predicted the concentration-time courses of FF in lung interstitial fluid, serum, and plasma following different dosing schedules, except at the dose of 15 mg/kg. When compared with the tissue residue data, the model generally underestimated the FF concentration at the injection site, whereas it gave good predictions of FF concentrations in lung, liver, and kidney at early time points. The model predictions provide a scientific basis for the dosage regimen design of FF.

Physiological parameter values for physiologically based pharmacokinetic models in food‐producing animals. Part I: Cattle and swine

“…For swine, the calculated mean relative organ weight of lungs was 0.9% (Table 9). This value is similar to the value of 1% for swine in previous review papers (Lin, Gehring, et al, 2016; Upton, 2008) and in one PBPK model for swine (Qian et al, 2017), and to the value of 0.8% in some recent PBPK models for swine (Li, Cheng, et al, 2019; Li et al, 2017).…”

“…As shown in Table 7, the weight of muscle is fairly constant and constitutes approximately 33.9% of the body weight in calves. The calculated mean relative tissue weight of muscle in swine was 36.32% (Table 9), which is close to the value of 40% reported in previous review papers (Lin, Gehring, et al, 2016; Upton, 2008) and some PBPK models for swine (Qian et al, 2017; Yuan, Luo, Zhu, Wang, & Liu, 2011), and similar to the value of 35.5% used in PBPK models for swine (Li, Cheng, et al, 2019; Li et al, 2017).…”

“…The calculated value was 34.2% of cardiac output in swine shown in Table 28. The value for blood flow fraction of muscle in swine is close to but slightly higher than the value of 29.3% used in PBPK models for swine (Li, Cheng, et al, 2019; Li et al, 2017) and the value of 25% reported in previous review papers (Lin, Gehring, et al, 2016; Upton, 2008) and some other PBPK models for swine (Qian et al, 2017; Yuan et al, 2011). The values of blood flow to muscle in mice, rats, dogs, and humans fall in the range of 16.1 to 29.7% (Brown et al, 1997).…”

Pharmacokinetics of florfenicol and its metabolite florfenicol amine in crucian carp (Carassius auratus) at three temperatures after one single intramuscular injection

“…Florfenicol (FF) is the latest generation of amphenicols and was specifically developed for veterinary use (Yang et al., ). It works by inhibiting the protein synthesis in susceptible bacteria (Qian et al., ). In vitro studies have shown that FF has potent activity against some bacterial species which are pathogenic to fish, including Vibrio anguillarum (Samuelsen, Bergh, & Ervik, ), Listonella anguillarum (Seljestokken et al., ), and Francisella asiatica (Soto, Endris, & Hawke, ).…”

Razvoj SPE-HPLC-DAD metode za određivanje florfenikola i florfenikol amina u cerebrospinalnoj tekućini svinja

“…Radiometric studies of 14 C-FF conducted in pigs following various routes of administration (EMA, 1999) showed that FF has a major fraction of radioactivity (45 to 60%) in urine, followed by florfenicol amine (FFA, 11.2 to 17%), its marker residue. In pharmacokinetic (PK) and pharmacodynamic (PD) studies of FF in pigs, peak plasma concentrations in the range from 3 to 12 µg/mL were reported within 5 hours of intramuscular administration (Voorspoels et al, 1999;Liu et al, 2003;Geng et al, 2015;Qian et al, 2017;de Smet et al, 2018;Lei et al, 2018). The dispositions of FF in cerebrospinal fluid (CSF) were studied mainly in calves.…”