Physiologically Based Pharmacokinetic Modeling of Cefadroxil in Mouse, Rat, and Human to Predict Concentration–Time Profile at Infected Tissue

Abstract

The aim of this study was to develop physiologically based pharmacokinetic (PBPK) models capable of simulating cefadroxil concentrations in plasma and tissues in mouse, rat, and human. PBPK models in this study consisted of 14 tissues and 2 blood compartments. They were established using measured tissue to plasma partition coefficient (Kp) in mouse and rat, absolute expression levels of hPEPT1 along the entire length of the human intestine, and the transporter kinetic parameters. The PBPK models also assumed that all the tissues were well-stirred compartments with perfusion rate limitations, and the ratio of the concentration in tissue to the unbound concentration in plasma is identical across species. These PBPK models were validated strictly by a series of observed plasma concentration–time profile data. The average fold error (AFE) and absolute average fold error (AAFE) values were all less than 2. The models’ rationality and accuracy were further demonstrated by the almost consistent Vss calculated by the PBPK model and noncompartmental method, as well as the good allometric scaling relationship of Vss and CL. The model suggests that hPEPT1 is the major transporter responsible for the oral absorption of cefadroxil in human, and the plasma concentration–time profiles of cefadroxil were not sensitive to dissolution rate faster than T85% = 2 h. The cefadroxil PBPK model in human is reliable and can be used to predict concentration–time profile at infected tissue. It may be useful for dose selection and informative decision-making during clinical trials and dosage form design of cefadroxil and provide a reference for the PBPK model establishment of hPEPT1 substrate.

Physiologically based pharmacokinetic modelling and simulation to predict the plasma concentration profile of schaftoside after oral administration of total flavonoids of Desmodium styracifolium

“…The FE i value of time at 12 h of model in rat simulating 100 mg/kg TFDS (literature report) was without 3-fold error (FE i = 4.47. These may be caused by experiment errors in the blood sampling or detection for the last time point ( Tan et al, 2021 ). In addition, the AFE and AAFE values for models in rat and human were all within 2-fold error ( Table 5 ).…”

“…The fold error of each point (FE i ), average fold error (AFE) and absolute average fold error (AAFE) were three commonly used test criteria to evaluate the accuracy of models ( Tan et al, 2021 ). FE i showed the predictive accuracy of data at time point i , as calculated in Eq.…”

Predicting transporter mediated drug–drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward

“…Kim et al., assuming involvement of novel transporters at the intestinal level, developed the PBPK model for bilastine (Kim et al., 2021). Other transporters, such as (peptide transporter 1) PEPT1 and (plasma membrane monoamine transporter) PMAT, were also being modeled, as they play a vital role for intestinal absorption of drugs such as cefadroxil, lisinopril, and metformin (Tan et al., 2021; Xie et al., 2021; Yang et al., 2021). Intestinal carnitine/organic cation transporter 2 and mono‐carboxylate transporter protein 1 that are distributed in gastrointestinal tract and brain are being explored, as they may aid in targeted drug delivery (Guo et al., 2020; Wang, Zhao, et al., 2020).…”