Development of a multiroute physiologically based pharmacokinetic model for orbifloxacin in rabbits

Abstract

To predict the orbifloxacin concentrations in rabbits after multiple routes of administration, a flow-limited multiroute physiologically based pharmacokinetic (PBPK) model was developed. Three routes of administration (IV, IM, and PO) were incorporated into this model. Physiological parameters including tissue weights and blood flows through different tissues were obtained from the literature. The tissue/plasma partition coefficients (P s) for noneliminating tissues were calculated according to the area method, while the P s for kidney and the rest of the body compartment, together with other parameters for absorption and elimination, were optimized based on the published concentrations. The comparisons between predicted and observed orbifloxacin concentrations proved its validity, and the present model predicted available concentration data well, including those in liver, kidney, muscle, lung, heart, and plasma after oral, intravenous, or intramuscular administration. A local sensitivity analysis was also performed, which showed that the parameters for oral absorption were most influential on the orbifloxacin concentrations. This model was used to predict plasma and tissue concentrations after multiple oral or intramuscular administration. This study demonstrated the feasibility of predicting drug residues in minor species after multiple routes of administration in the extra-label manner using the PBPK modeling.

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

“…In the last decade, PBPK modeling has been widely used in the area of veterinary medicine, from the prediction of drug tissue residues (Huang et al, ; Leavens et al, ; Yang et al, ), estimating the withdrawal time (Buur, Baynes, Smith, & Riviere, ; Yang, Huang, et al, ; Yang, Zhou, et al, ), to facilitating the food safety assessment (Henri, Carrez, Meda, Laurentie, & Sanders, ; Lin, Gehring, Mochel, Lavé, & Riviere, ; Yang, Huang, et al, ; Yang, Zhou, et al, ). In this study, a PBPK model was established for heavy sows based on a previous generic PBPK model for swine and cattle (Li et al, ).…”

Development and Application of a Water Temperature Related Physiologically Based Pharmacokinetic Model for Enrofloxacin and Its Metabolite Ciprofloxacin in Rainbow Trout

“…During the immersion bath, the drug was assumed to be only absorbed from the gill to the blood circulation, with the absorption rate constant of K aIB and a complete 100% absorption (Figure 1). For the PO route, a two-compartment model including stomach and gut was applied to simulate the absorption based on our previous study (26). It was assumed that ENR entered the stomach directly and then was transported into the gut through gastric emptying at the rate of K st .…”

“…Following IV injection or extravascular absorption, ENR was distributed through the bloodstream to all tissue compartments. As reported anywhere (26,28,29,41), the mass balance equations were coded to describe the concentration or mass change for ENR or CIP in each compartment (Table 2). According to the previous report (23), ENR is mainly eliminated by liver metabolism and renal excretion.…”

“…A sensitivity analysis was carried out according to the previous study (41). In the sensitivity analysis process, the central difference method was utilized; more details could be found in our previous studies (26,41). If the absolute value of its NSC was >0.25 (41), this parameter was considered as an influential one.…”

“…There have been increasing studies on predicting veterinary drug residues (24)(25)(26)(27) and drug withdrawal periods (21,(28)(29)(30)(31) based on the PBPK model. The PBPK model is based on the mass balance equation and allows the application of population variability data and in vitro mechanism to predict drug concentration in edible tissues (32).…”