{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T16:51:07Z","timestamp":1772729467842,"version":"3.50.1"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32273063"],"award-info":[{"award-number":["32273063"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National key research and development program","doi-asserted-by":"crossref","award":["2022YFD1800400"],"award-info":[{"award-number":["2022YFD1800400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Cefquinome is widely used to treat respiratory tract diseases of swine. While extra-label dosages of cefquinome could improve clinical efficacy, they might lead to excessively high residues in animal-derived food. In this study, a physiologically based pharmacokinetic (PBPK) model was calibrated based on the published data and a microdialysis experiment to assess the dosage efficiency and food safety. For the microdialysis experiment,<jats:italic>in vitro<\/jats:italic>\/<jats:italic>in vivo<\/jats:italic>relative recovery and concentration-time curves of cefquinome in the lung interstitium were investigated. This PBPK model is available to predict the drug concentrations in the muscle, kidney, liver, plasma, and lung interstitial fluid. Concentration-time curves of 1000 virtual animals in different tissues were simulated by applying sensitivity and Monte Carlo analyses. By integrating pharmacokinetic\/pharmacodynamic target parameters, cefquinome delivered at 3\u20135 mg\/kg twice daily is advised for the effective control of respiratory tract infections of nursery pig, which the bodyweight is around 25 kg. Based on the predicted cefquinome concentrations in edible tissues, the withdrawal interval is 2 and 3 days for label and the extra-label doses, respectively. This study provides a useful tool to optimize the dosage regimen of cefquinome against respiratory tract infections and predicts the concentration of cefquinome residues in edible tissues. This information would be helpful to improve the food safety and guide rational drug usage.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011331","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T17:25:11Z","timestamp":1692206711000},"page":"e1011331","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["A physiologically based pharmacokinetic model to optimize the dosage regimen and withdrawal time of cefquinome in pigs"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7058-1849","authenticated-orcid":true,"given":"Kun","family":"Mi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixuan","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaixiang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyue","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanhu","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9055-5158","authenticated-orcid":true,"given":"Lingli","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"key":"pcbi.1011331.ref001","unstructured":"CVMP. Cefquinome (Extension to Pigs). Summary Report (2). EMEA\/MRL\/545\/99-FINAL. 1999;European Agency for the Evaluation of Medicinal Products, London, UK."},{"key":"pcbi.1011331.ref002","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/bs.ampbs.2020.12.001","article-title":"Actinobacillus pleuropneumoniae: The molecular determinants of virulence and pathogenesis","volume":"78","author":"N Nahar","year":"2021","journal-title":"Advances in microbial physiology"},{"key":"pcbi.1011331.ref003","first-page":"9","article-title":"Antimicrobial Susceptibility Pattern of Porcine Respiratory Bacteria in Spain","author":"A Vilar\u00f3","year":"2020","journal-title":"Antibiotics (Basel, Switzerland)"},{"issue":"Pt A","key":"pcbi.1011331.ref004","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.fct.2017.06.023","article-title":"Development and application of a population physiologically based pharmacokinetic model for penicillin G in swine and cattle for food safety assessment","volume":"107","author":"M Li","year":"2017","journal-title":"Food and chemical toxicology"},{"issue":"7","key":"pcbi.1011331.ref005","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1007\/s00204-019-02464-z","article-title":"Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration.","volume":"93","author":"M Li","year":"2019","journal-title":"Archives of toxicology"},{"key":"pcbi.1011331.ref006","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.fct.2015.12.020","article-title":"Health concerns and management of select veterinary drug residues","volume":"88","author":"RE Baynes","year":"2016","journal-title":"Food and chemical toxicology"},{"issue":"12","key":"pcbi.1011331.ref007","first-page":"2002","article-title":"Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling.","volume":"32","author":"L Huang","year":"2015","journal-title":"Food additives & contaminants Part A, Chemistry, analysis, control, exposure & risk assessment."},{"issue":"6","key":"pcbi.1011331.ref008","doi-asserted-by":"crossref","first-page":"e30","DOI":"10.1111\/jvp.12419","article-title":"Diffusion-limited PBPK model for predicting pulmonary pharmacokinetics of florfenicol in pig","volume":"40","author":"MR Qian","year":"2017","journal-title":"Journal Of Veterinary Pharmacology And Therapeutics"},{"issue":"2","key":"pcbi.1011331.ref009","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2217\/nnm.15.177","article-title":"A computational framework for interspecies pharmacokinetics, exposure and toxicity assessment of gold nanoparticles.","volume":"11","author":"Z Lin","year":"2016","journal-title":"Nanomedicine (London, England)."},{"issue":"2","key":"pcbi.1011331.ref010","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/jvp.12917","article-title":"The pharmacokinetic\/pharmacodynamic paradigm for antimicrobial drugs in veterinary medicine: Recent advances and critical appraisal","volume":"44","author":"PL Toutain","year":"2021","journal-title":"Journal of veterinary pharmacology and therapeutics"},{"issue":"1","key":"pcbi.1011331.ref011","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1128\/AAC.02006-13","article-title":"Terbinafine in combination with other antifungal agents for treatment of resistant or refractory mycoses: investigating optimal dosing regimens using a physiologically based pharmacokinetic model","volume":"58","author":"MJ Dolton","year":"2014","journal-title":"Antimicrobial agents and chemotherapy"},{"issue":"8","key":"pcbi.1011331.ref012","article-title":"Apply a Physiologically Based Pharmacokinetic Model to Promote the Development of Enrofloxacin Granules: Predict Withdrawal Interval and Toxicity Dose.","volume":"10","author":"K Zhou","year":"2021","journal-title":"Antibiotics (Basel, Switzerland)."},{"issue":"4","key":"pcbi.1011331.ref013","doi-asserted-by":"crossref","first-page":"115292","DOI":"10.1016\/j.diagmicrobio.2020.115292","article-title":"Comparing probability of target attainment against Staphylococcus aureus for ceftaroline fosamil, vancomycin, daptomycin, linezolid, and ceftriaxone in complicated skin and soft tissue infection using pharmacokinetic\/pharmacodynamic models","volume":"99","author":"A Cristinacce","year":"2021","journal-title":"Diagnostic microbiology and infectious disease"},{"key":"pcbi.1011331.ref014","author":"FDA","year":"2016","journal-title":"Guidance for Industry #3, General Principles for Evaluating the Human Food Safety of New Animal Drugs Used in Food-producing Animals."},{"key":"pcbi.1011331.ref015","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.fct.2019.02.029","article-title":"Development and application of a population physiologically based pharmacokinetic model for florfenicol and its metabolite florfenicol amine in cattle","volume":"126","author":"F Yang","year":"2019","journal-title":"Food and chemical toxicology"},{"issue":"3","key":"pcbi.1011331.ref016","doi-asserted-by":"crossref","first-page":"37004","DOI":"10.1289\/EHP7671","article-title":"Development of a Gestational and Lactational Physiologically Based Pharmacokinetic (PBPK) Model for Perfluorooctane Sulfonate (PFOS) in Rats and Humans and Its Implications in the Derivation of Health-Based Toxicity Values.","volume":"129","author":"WC Chou","year":"2021","journal-title":"Environmental health perspectives"},{"issue":"8","key":"pcbi.1011331.ref017","article-title":"Determination of Susceptibility Breakpoint for Cefquinome against Streptococcus suis in Pigs.","volume":"10","author":"K Mi","year":"2021","journal-title":"Antibiotics (Basel, Switzerland)."},{"issue":"25","key":"pcbi.1011331.ref018","doi-asserted-by":"crossref","first-page":"10493","DOI":"10.1021\/jf0719860","article-title":"Residue depletion of cefquinome in swine tissues after intramuscular administration","volume":"55","author":"X Zhang","year":"2007","journal-title":"Journal of agricultural and food chemistry"},{"issue":"6","key":"pcbi.1011331.ref019","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/j.1365-2885.2008.00989.x","article-title":"Pharmacokinetics and bioavailability of cefquinome in healthy piglets","volume":"31","author":"XB Li","year":"2008","journal-title":"Journal of veterinary pharmacology and therapeutics"},{"issue":"1","key":"pcbi.1011331.ref020","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/toxsci\/kfx070","article-title":"Performance Assessment and Translation of Physiologically Based Pharmacokinetic Models From acslX to Berkeley Madonna, MATLAB, and R Language: Oxytetracycline and Gold Nanoparticles As Case Examples","volume":"158","author":"Z Lin","year":"2017","journal-title":"Toxicological sciences"},{"key":"pcbi.1011331.ref021","first-page":"193","article-title":"Residue deleption of cefquinome injection in pigs.","volume":"6","author":"X Xu","year":"2008","journal-title":"Journal of Jiangsu Agricultural Sciences"},{"key":"pcbi.1011331.ref022","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.3389\/fmicb.2017.02344","article-title":"En route towards European clinical breakpoints for veterinary antimicrobial susceptibility testing: a position paper explaining the VetCAST approach.","volume":"8","author":"P-L Toutain","year":"2017","journal-title":"Frontiers in microbiology"},{"key":"pcbi.1011331.ref023","article-title":"Cefquinome.","author":"CVMP","year":"1995","journal-title":"Summary report. EMEA\/MRL\/005\/95."},{"issue":"1","key":"pcbi.1011331.ref024","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41370-018-0046-9","article-title":"Advancing internal exposure and physiologically-based toxicokinetic modeling for 21st-century risk assessments","volume":"29","author":"EA Cohen Hubal","year":"2019","journal-title":"Journal of exposure science & environmental epidemiology"},{"key":"pcbi.1011331.ref025","article-title":"Physiologically based pharmacokinetic analyses\u2014format and content.","author":"FDA","year":"2018","journal-title":"Guidance for Industry"},{"issue":"5","key":"pcbi.1011331.ref026","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s11095-018-2379-4","article-title":"A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion","volume":"35","author":"A Viel","year":"2018","journal-title":"Pharmaceutical research"},{"issue":"2","key":"pcbi.1011331.ref027","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1208\/s12248-012-9446-2","article-title":"Dose selection based on physiologically based pharmacokinetic (PBPK) approaches.","volume":"15","author":"HM Jones","year":"2013","journal-title":"The AAPS journal"},{"issue":"5","key":"pcbi.1011331.ref028","doi-asserted-by":"crossref","DOI":"10.3390\/pharmaceutics13050602","article-title":"Application of a Physiologically Based Pharmacokinetic Model to Develop a Veterinary Amorphous Enrofloxacin Solid Dispersion.","volume":"13","author":"K Zhou","year":"2021","journal-title":"Pharmaceutics."},{"issue":"3","key":"pcbi.1011331.ref029","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.vascn.2008.08.001","article-title":"Organ weights and blood flows of sheep and pig for physiological pharmacokinetic modelling","volume":"58","author":"RN Upton","year":"2008","journal-title":"Journal of pharmacological and toxicological methods"},{"issue":"4","key":"pcbi.1011331.ref030","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/jvp.12938","article-title":"Physiological parameter values for physiologically based pharmacokinetic models in food-producing animals. Part III: Sheep and goat","volume":"44","author":"M Li","year":"2021","journal-title":"Journal of veterinary pharmacology and therapeutics"},{"key":"pcbi.1011331.ref031","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.vascn.2015.11.007","article-title":"Penetration of antimicrobials to pulmonary epithelial lining fluid and muscle and impact of drug physicochemical properties determined by microdialysis","volume":"78","author":"LA Rottb\u00f8ll","year":"2016","journal-title":"Journal of pharmacological and toxicological methods"},{"issue":"8","key":"pcbi.1011331.ref032","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1289\/ehp.1206001","article-title":"Understanding and managing zoonotic risk in the new livestock industries","volume":"121","author":"M Liverani","year":"2013","journal-title":"Environmental health perspectives"},{"issue":"1","key":"pcbi.1011331.ref033","doi-asserted-by":"crossref","first-page":"9908","DOI":"10.1038\/s41598-019-45482-8","article-title":"Prevalence and antimicrobial susceptibilities of bacterial pathogens in Chinese pig farms from 2013 to 2017.","volume":"9","author":"B Zhang","year":"2019","journal-title":"Scientific reports."},{"key":"pcbi.1011331.ref034","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.vetmic.2019.02.034","article-title":"Investigation of Haemophilus parasuis from healthy pigs in China","volume":"231","author":"P Zhang","year":"2019","journal-title":"Veterinary microbiology"},{"key":"pcbi.1011331.ref035","doi-asserted-by":"crossref","first-page":"5465678","DOI":"10.1155\/2016\/5465678","article-title":"Application of PK\/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction.","volume":"2016","author":"I Ahmad","year":"2016","journal-title":"BioMed research international."},{"issue":"1","key":"pcbi.1011331.ref036","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1086\/516284","article-title":"Pharmacokinetic\/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men","volume":"26","author":"WA Craig","year":"1998","journal-title":"Clinical infectious diseases"},{"key":"pcbi.1011331.ref037","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.coph.2017.09.009","article-title":"Use of Monte Carlo simulation and considerations for PK-PD targets to support antibacterial dose selection","volume":"36","author":"M Trang","year":"2017","journal-title":"Current opinion in pharmacology"},{"issue":"3","key":"pcbi.1011331.ref038","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s10928-007-9053-5","article-title":"Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs","volume":"34","author":"S Willmann","year":"2007","journal-title":"Journal of pharmacokinetics and pharmacodynamics"},{"issue":"4","key":"pcbi.1011331.ref039","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/jvp.12766","article-title":"An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows","volume":"42","author":"M Li","year":"2019","journal-title":"Journal of veterinary pharmacology and therapeutics"},{"key":"pcbi.1011331.ref040","doi-asserted-by":"crossref","first-page":"111127","DOI":"10.1016\/j.fct.2020.111127","article-title":"A physiologically based pharmacokinetic model of doxycycline for predicting tissue residues and withdrawal intervals in grass carp (Ctenopharyngodon idella).","volume":"137","author":"N Xu","year":"2020","journal-title":"Food and chemical toxicology"},{"issue":"5","key":"pcbi.1011331.ref041","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1111\/jvp.12387","article-title":"Lung microdialysis study of florfenicol in pigs after single intramuscular administration","volume":"40","author":"B Yang","year":"2017","journal-title":"Journal of veterinary pharmacology and therapeutics"},{"issue":"4","key":"pcbi.1011331.ref042","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/bcpt.12403","article-title":"Intrabronchial Microdialysis: Effects of Probe Localization on Tissue Trauma and Drug Penetration into the Pulmonary Epithelial Lining Fluid.","volume":"117","author":"LA Rottb\u00f8ll","year":"2015","journal-title":"Basic & clinical pharmacology & toxicology"},{"issue":"3","key":"pcbi.1011331.ref043","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.tvjl.2013.12.015","article-title":"Pharmacokinetics and ex vivo pharmacodynamics of cefquinome in porcine serum and tissue cage fluids","volume":"199","author":"BX Zhang","year":"2014","journal-title":"Veterinary journal (London, England: 1997)."},{"issue":"1","key":"pcbi.1011331.ref044","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/jps.24244","article-title":"Development and application of a multiroute physiologically based pharmacokinetic model for oxytetracycline in dogs and humans","volume":"104","author":"Z Lin","year":"2015","journal-title":"Journal of pharmaceutical sciences"},{"issue":"2","key":"pcbi.1011331.ref045","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1093\/toxsci\/kfab095","article-title":"Development and Application of an interactive Physiologically Based Pharmacokinetic (iPBPK) Model to Predict Oxytetracycline Tissue Distribution and Withdrawal Intervals in Market-Age Sheep and Goats.","volume":"183","author":"MH Riad","year":"2021","journal-title":"Toxicological sciences"},{"issue":"1","key":"pcbi.1011331.ref046","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1080\/10717544.2017.1321058","article-title":"Preparation and testing of cefquinome-loaded poly lactic-co-glycolic acid microspheres for lung targeting","volume":"24","author":"S Qu","year":"2017","journal-title":"Drug delivery"},{"key":"pcbi.1011331.ref047","volume-title":"Characterization and application of physiologically based pharmacokinetic models in risk assessment.","author":"WHO","year":"2010"},{"issue":"2","key":"pcbi.1011331.ref048","article-title":"Evidence for Establishing the Clinical Breakpoint of Cefquinome against Haemophilus Parasuis in China.","volume":"10","author":"K Mi","year":"2021","journal-title":"Pathogens (Basel, Switzerland)."},{"issue":"3\u20134","key":"pcbi.1011331.ref049","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.vetmic.2014.02.004","article-title":"Resistance to selected beta-lactam antibiotics","volume":"171","author":"K Nedbalcova","year":"2014","journal-title":"Veterinary microbiology"},{"issue":"1","key":"pcbi.1011331.ref050","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1093\/toxsci\/kfy067","article-title":"Probabilistic Physiologically Based Pharmacokinetic Model for Penicillin G in Milk From Dairy Cows Following Intramammary or Intramuscular Administrations","volume":"164","author":"M Li","year":"2018","journal-title":"Toxicological sciences"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011331","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T04:42:10Z","timestamp":1702960930000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011331"}},"subtitle":[],"editor":[{"given":"James","family":"Gallo","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,16]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011331","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,16]]}}}