{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:43:20Z","timestamp":1792799000734,"version":"4.5.0"},"reference-count":59,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The search for new drugs is an extremely time-consuming and expensive endeavour. Much of that time and money go into generating predictive human pharmacokinetic profiles from preclinical efficacy and safety animal data. These pharmacokinetic profiles are used to prioritize or minimize the attrition at later stages of the drug discovery process. In the area of antiviral drug research, these pharmacokinetic profiles are equally important for the optimization, estimation of half-life, determination of effective dose, and dosing regimen, in humans. In this article we have highlighted three important aspects of these profiles. First, the impact of plasma protein binding on two primary pharmacokinetic parameters\u2014volume of distribution and clearance. Second, interdependence of primary parameters on unbound fraction of the drug. Third, the ability to extrapolate human pharmacokinetic parameters and concentration time profiles from animal profiles.<\/jats:p>","DOI":"10.3390\/pharmaceutics15041212","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T01:35:08Z","timestamp":1681263308000},"page":"1212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["ADME, Pharmacokinetic Scaling, Pharmacodynamic and Prediction of Human Dose and Regimen of Novel Antiviral Drugs"],"prefix":"10.3390","volume":"15","author":[{"given":"Tridib","family":"Chaira","sequence":"first","affiliation":[{"name":"Department of Pharmacology, SGT University, Gurugram 122505, Haryana, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5002-3807","authenticated-orcid":false,"given":"Chandru","family":"Subramani","sequence":"additional","affiliation":[{"name":"Department of Pathology, Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4121-4526","authenticated-orcid":false,"given":"Tarani Kanta","family":"Barman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/S1359-6446(97)01099-4","article-title":"Managing the drug discovery\/development interface","volume":"2","author":"Kennedy","year":"1997","journal-title":"Drug Discov. Today"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1208\/s12248-012-9353-6","article-title":"ADME of Biologics\u2014What Have We Learned from Small Molecules?","volume":"14","author":"Prueksaritanont","year":"2012","journal-title":"AAPS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3966","DOI":"10.1128\/AAC.49.9.3966-3969.2005","article-title":"Nevirapine plasma exposure affects both durability of viral suppression and selection of nevirapine primary resistance mutations in a clinical setting","volume":"49","author":"Bonora","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1365-2125.2004.02240.x","article-title":"Pharmacokinetics of saquinavir hard gel\/ritonavir (1000\/100 mg twice daily) when administered with tenofovir diproxil fumarate in HIV-1-infected subjects","volume":"59","author":"Boffito","year":"2005","journal-title":"Br. J. Clin. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1089\/aid.2013.0031","article-title":"Increasing Extracellular Protein Concentration Reduces Intracellular Antiretroviral Drug Concentration and Antiviral Effect","volume":"29","author":"Avery","year":"2013","journal-title":"Aids Res. Hum. Retrovir."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1097\/00042560-199705010-00005","article-title":"Phase I\/II study of the toxicity, pharmacokinetics, and activity of the HIV protease inhibitor SC-52151","volume":"15","author":"Fischl","year":"1997","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_7","unstructured":"Keogh, J.H., Rynn, B.C., Bruno Stieger, B., and Nicholls, G. (2016). Membrane Transporters: Fundamentals, Function and Their Role in ADME and Drug Development, Royal Society of Chemistry."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3769\/radioisotopes.26.3_151","article-title":"Absorption, distribution, excretion and metabolism of SC-11800EE, a combined steroid preparation of SC-11800 (ethynodiol diacetate) and ethinyl estradiol in rats and mice","volume":"26","author":"Suzuki","year":"1977","journal-title":"Radioisotopes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1002\/jps.23614","article-title":"Plasma protein binding: From discovery to development","volume":"102","author":"Bohnert","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14866","DOI":"10.1038\/srep14866","article-title":"Characterization of plasma protein binding dissociation with online SPE-HPLC","volume":"5","author":"Li","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_11","first-page":"47","article-title":"A technical view on transporters-the drug pharmacokinetics dictators","volume":"9","author":"Anusha","year":"2019","journal-title":"MOJ Bioequiv. Availab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.1002\/jcph.703","article-title":"Role of Hepatic Drug Transporters in Drug Development","volume":"56","author":"Liu","year":"2016","journal-title":"J. Clin. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.tips.2004.02.007","article-title":"Pharmacogenetics of cytochrome P450 and its applications in drug therapy: The past, present and future","volume":"25","year":"2004","journal-title":"Trends Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharm. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1097\/FPC.0000000000000172","article-title":"Genetic variation in the human cytochrome P450 supergene family","volume":"25","author":"Fujikura","year":"2015","journal-title":"Pharm. Genom."},{"key":"ref_16","first-page":"284","article-title":"The genetic landscape of major drug metabolizing cytochrome P450 genes\u2014An updated analysis of population-scale sequencing data","volume":"22","author":"Zhou","year":"2022","journal-title":"Pharm. J."},{"key":"ref_17","first-page":"570","article-title":"Implications of polymorphic cytochrome p450-dependent drug metabolism for drug development","volume":"29","year":"2001","journal-title":"Drug Metab. Dispos."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/03602530902843483","article-title":"Polymorphism of human cytochrome P450 enzymes and its clinical impact","volume":"41","author":"Zhou","year":"2009","journal-title":"Drug Metab. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1007\/s40262-016-0407-2","article-title":"Drug\u2013drug interactions between direct-acting antivirals and psychoactive medications","volume":"55","author":"Smolders","year":"2016","journal-title":"Clin. Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1080\/17425255.2019.1604685","article-title":"Pharmacokinetics and pharmacodynamics of cytochrome P450 inhibitors for HIV treatment","volume":"15","author":"Gong","year":"2019","journal-title":"Expert. Opin. Drug Metab. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1136\/ejhpharm-2020-002390","article-title":"Fighting on two fronts: Drug\u2013drug interactions in people living with HIV infected with SARS-CoV-2","volume":"28","author":"Bahap","year":"2020","journal-title":"Eur. J. Hosp. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yagura, H., Watanabe, D., Kushida, H., Tomishima, K., Togami, H., Hirano, A., Takahashi, M., Hirota, K., Ikuma, M., and Kasai, D. (2017). Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1. BMC Infect. Dis., 17.","DOI":"10.1186\/s12879-017-2717-x"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7359","DOI":"10.1038\/s41598-018-25803-z","article-title":"Impact of UGT1A1 polymorphisms on Raltegravir and its glucuronide plasma concentrations in a cohort of HIV-1 infected patients","volume":"8","author":"Belkhir","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s40262-015-0260-8","article-title":"Clinical pharmacology profile of boceprevir, a hepatitis C virus NS3 protease inhibitor: Focus on drug-drug interactions","volume":"54","author":"Khalilieh","year":"2015","journal-title":"Clin. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/j.1365-2125.2008.03137.x","article-title":"Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects","volume":"65","author":"Abel","year":"2008","journal-title":"Br. J. Clin. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1517\/17425255.2014.934671","article-title":"The application of allometric scaling principles to predict pharmacokinetic parameters across species","volume":"10","author":"Huang","year":"2014","journal-title":"Expert. Opin. Drug Metab. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1208\/s12249-019-1434-8","article-title":"Prediction of Human Pharmacokinetics of Fomepizole from Preclinical Species Pharmacokinetics Based on Normalizing Time Course Profiles","volume":"20","author":"Jairam","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"887","DOI":"10.3109\/00498259609052491","article-title":"Interspecies scaling: Predicting clearance of drugs in humans. Three different approaches","volume":"26","author":"Mahmood","year":"1996","journal-title":"Xenobiotica"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1124\/dmd.105.004143","article-title":"A novel model for prediction of human drug clearance by allometric scaling","volume":"33","author":"Tang","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/j.1365-2885.2006.00786.x","article-title":"Interspecies allometric scaling. Part I: Prediction of clearance in large animals","volume":"29","author":"Mahmood","year":"2006","journal-title":"J. Vet. Pharm. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/BF01061720","article-title":"Prediction of the disposition of beta-lactam antibiotics in humans from pharmacokinetic parameters in animals","volume":"12","author":"Sawada","year":"1984","journal-title":"J. Pharm. Biopharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1002\/jps.2600751104","article-title":"Man versus beast: Pharmacokinetic scaling in mammals","volume":"75","author":"Mordenti","year":"1986","journal-title":"J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.3109\/03602538308991421","article-title":"Evolutionary biology, animal behavior, fourth-dimensional space, and the raison d\u2019etre of drug metabolism and pharmacokinetics","volume":"14","author":"Boxenbaum","year":"1983","journal-title":"Drug Metab. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.3109\/03602538409033558","article-title":"Interspecies pharmacokinetic scaling and the evolutionary-comparative paradigm","volume":"15","author":"Boxenbaum","year":"1984","journal-title":"Drug Metab. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"206","DOI":"10.18433\/jpps30942","article-title":"In Vitro ADME, Preclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of RBx14255, a Novel Ketolide with Pharmacodynamics Against Multidrug-Resistant Bacterial Pathogens","volume":"23","author":"Chaira","year":"2020","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/(SICI)1099-081X(199904)20:3<137::AID-BDD165>3.0.CO;2-I","article-title":"A comparative study of allometric scaling with plasma concentrations predicted by species-invariant time methods","volume":"20","author":"Mahmood","year":"1999","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1128\/jb.59.5.625-643.1950","article-title":"The effective concentrations of penicillin in vitro and in vivo for streptococci, pneumococci, and Treponema pallidum","volume":"59","author":"Eagle","year":"1950","journal-title":"J. Bacteriol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/0002-9343(50)90425-6","article-title":"Effect of schedule of administration on the therapeutic efficacy of penicillin; importance of the aggregate time penicillin remains at effectively bactericidal levels","volume":"9","author":"Eagle","year":"1950","journal-title":"Am. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1086\/510079","article-title":"Pharmacokinetics-pharmacodynamics of antimicrobial therapy: It\u2019s not just for mice anymore","volume":"44","author":"Ambrose","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_41","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":"Craig","year":"1998","journal-title":"Clin. Infect. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S1369-5274(00)00132-6","article-title":"Pharmacodynamics in the study of drug resistance and establishing in vitro susceptibility breakpoints: Ready for prime time","volume":"3","author":"Dudley","year":"2000","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rodriguez-Gascon, A., Solinis, M.A., and Isla, A. (2021). The Role of PK\/PD Analysis in the Development and Evaluation of Antimicrobials. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060833"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1128\/AAC.45.10.2793-2797.2001","article-title":"Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections","volume":"45","author":"Ambrose","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jiac.2015.02.001","article-title":"Applications of the pharmacokinetic\/pharmacodynamic (PK\/PD) analysis of antimicrobial agents","volume":"21","author":"Isla","year":"2015","journal-title":"J. Infect. Chemother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s40265-018-0891-9","article-title":"Individualising Therapy to Minimize Bacterial Multidrug Resistance","volume":"78","author":"Heffernan","year":"2018","journal-title":"Drugs"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1007\/s40262-020-00892-0","article-title":"Preclinical Pharmacokinetic\/Pharmacodynamic Studies and Clinical Trials in the Drug Development Process of EMA-Approved Antibacterial Agents: A Review","volume":"59","author":"Jorda","year":"2020","journal-title":"Clin. Pharm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s10156-003-0279-X","article-title":"Optimizing outcomes with antimicrobial therapy through pharmacodynamic profiling","volume":"9","author":"Nicolau","year":"2003","journal-title":"J. Infect. Chemother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/nrmicro862","article-title":"Antimicrobial pharmacodynamics: Critical interactions of \u2018bug and drug\u2019","volume":"2","author":"Drusano","year":"2004","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3851\/IMP1770","article-title":"Antiviral pharmacodynamics in hollow fibre bioreactors","volume":"21","author":"McSharry","year":"2011","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2165\/11534730-000000000-00000","article-title":"Oseltamivir in seasonal, avian H5N1 and pandemic 2009 A\/H1N1 influenza: Pharmacokinetic and pharmacodynamic characteristics","volume":"49","author":"Widmer","year":"2010","journal-title":"Clin. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2165\/00003088-199937060-00003","article-title":"Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802","volume":"37","author":"He","year":"1999","journal-title":"Clin. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1128\/AAC.42.3.640","article-title":"Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection","volume":"42","author":"Mendel","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0166-3542(00)00125-X","article-title":"In vitro and in vivo assay systems for study of influenza virus inhibitors","volume":"48","author":"Sidwell","year":"2000","journal-title":"Antivir. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1128\/AAC.00167-09","article-title":"Prediction of the pharmacodynamically linked variable of oseltamivir carboxylate for influenza A virus using an in vitro hollow-fiber infection model system","volume":"53","author":"McSharry","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1128\/AAC.45.7.2115-2118.2001","article-title":"Pharmacodynamic evaluation of RWJ-270201, a novel neuraminidase inhibitor, in a lethal murine model of influenza predicts efficacy for once-daily dosing","volume":"45","author":"Drusano","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1128\/AAC.01628-10","article-title":"Zanamivir, at 600 milligrams twice daily, inhibits oseltamivir-resistant 2009 pandemic H1N1 influenza virus in an in vitro hollow-fiber infection model system","volume":"55","author":"Brown","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_58","first-page":"46","article-title":"The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data","volume":"283","author":"Obach","year":"1997","journal-title":"J. Pharm. Exp. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Sharma, A., Benbrook, D.M., and Woo, S. (2018). Pharmacokinetics and interspecies scaling of a novel, orally-bioavailable anti-cancer drug, SHetA2. 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