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

Zhongxia Tan,Le Sun,Chao Wang,Youxi Zhang

doi:10.3389/fphar.2021.692741

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 (K p) 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 V ss calculated by the PBPK model and noncompartmental method, as well as the good allometric scaling relationship of V ss 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.

Highlights

Cefadroxil, a first-generation cephalosporin, has been commonly used in the treatment of different kinds of infections including urinary tract, skin, and respiratory infections (Tanrisever and Santella, 1986)
The predicted and observed plasma concentrations of cefadroxil obtained from the physiologically based pharmacokinetic (PBPK) models in mouse, rat, and human are present in Figure 3, Figure 4, and Figure 5
The models’ rationality and accuracy were further demonstrated by the almost consistent Vss calculated by different methods, good allometric scaling relationship of Vss and CL, and model Parameter sensitivity analysis (PSA)

Summary

Introduction

Cefadroxil, a first-generation cephalosporin, has been commonly used in the treatment of different kinds of infections including urinary tract, skin, and respiratory infections (Tanrisever and Santella, 1986). Cefadroxil has a high bioavailability (Santella and Henness, 1982) despite its poor lipophilicity. It is a substrate of the peptide transporter PEPT1, and PEPT1 plays an important role in its intestinal absorption (Posada and Smith, 2013b). Some tissue distribution data in human have been published (Nightingale, 1986; Akimoto et al, 1994; Nungu et al, 1995). They were only the concentration ratios of tissue/serum (plasma) at the peak time or other one time point. This did not reflect well the distribution of the drug in tissues

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