{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:00:35Z","timestamp":1789984835051,"version":"4.0.1"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["ORF-2026-131"],"award-info":[{"award-number":["ORF-2026-131"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]},{"award":["ORF-2026-131"],"award-info":[{"award-number":["ORF-2026-131"]}],"id":[{"id":"https:\/\/ror.org\/02f81g417","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Physiologically based pharmacokinetic (PBPK) modeling is an established approach used in recent years for estimating drug disposition in challenging clinical scenarios where in vivo studies are difficult to perform. Metoclopramide is a benzamide derivative, widely indicated for its antiemetic and prokinetic actions. This study aims to develop a PBPK model for metoclopramide in infants to predict its systemic exposure in this population. Methods: To develop the model, a detailed literature review was conducted, and the required data related to the drug, human physiology, and published clinical studies were retrieved. After that, all information was integrated into the PK-Sim software, and the model was initially developed in adults to create a base; subsequently, it was extrapolated to infants. After successful development, these models were verified visually and numerically using visual predictive checks (VPCs), mean predicted-to-observed ratios (Rpre\/obs), average fold error (AFE), and mean relative deviation (MRD). Results: All simulated profiles were consistent with observed data; computed AFE and Rpre\/obs for key pharmacokinetic (PK) parameters, including area under the concentration\u2013time curve from 0 to t (AUC0\u2013t), maximum plasma concentration (Cmax), and clearance (CL), fell within an acceptable two-fold error range. Moreover, the MRD values for all profiles were &lt;2, showing promising agreement between the reported and predicted datasets. Conclusions: The current model provides a robust framework to estimate the PK of metoclopramide in infants, which may help with dose individualization in this vulnerable population.<\/jats:p>","DOI":"10.3390\/ph19091482","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1482","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development and Evaluation of Physiologically Based Pharmacokinetic (PBPK) Models of Metoclopramide Across the Lifespan: Translation from Adults to Infants"],"prefix":"10.3390","volume":"19","author":[{"given":"Iqra","family":"Shahzad","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice, Faculty of Pharmacy, Bahhaudin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Ammara","family":"Zamir","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Faculty of Pharmacy, Bahhaudin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8607-8583","authenticated-orcid":false,"given":"Muhammad Fawad","family":"Rasool","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Faculty of Pharmacy, Bahhaudin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6450-0803","authenticated-orcid":false,"given":"Ali A.","family":"Alshamrani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"}]},{"given":"Iltaf","family":"Hussain","sequence":"additional","affiliation":[{"name":"Center for Drug Safety and Policy, Xi\u2019an Jiatong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-593X","authenticated-orcid":false,"given":"Faleh","family":"Alqahtani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1208\/s12248-026-01220-3","article-title":"Physiologically Based Pharmacokinetic (PBPK) Modeling of Oral Drug Absorption for Integrating Nonclinical Data into Human Pharmacokinetic Predictions","volume":"28","author":"Liang","year":"2026","journal-title":"AAPS J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"907461","DOI":"10.1155\/2011\/907461","article-title":"Physiologically based pharmacokinetic modeling: Methodology, applications, and limitations with a focus on its role in pediatric drug development","volume":"2011","author":"Khalil","year":"2011","journal-title":"BioMed Res. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/bdd.1769","article-title":"Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: Strategy and approach during the drug discovery phase with four case studies","volume":"33","author":"Chen","year":"2012","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1111\/j.1365-2125.2004.02225.x","article-title":"Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: Theophylline and midazolam as model drugs","volume":"59","year":"2005","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zamir, A., Rasool, M.F., Alqahtani, F., Alqhtani, H., and Ahmad, T. (2024). Integration of Ontogeny-Based Changes for Predicting the Exposure of Diphenhydramine in the Pediatric Population: A PBPK Modeling Approach. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16121553"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s12272-023-01472-z","article-title":"Physiologically based pharmacokinetic (PBPK) modeling to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes","volume":"46","author":"Cho","year":"2023","journal-title":"Arch. Pharmacal Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/jcph.6120","article-title":"Simultaneously Predicting Pharmacokinetics of Loratadine and Desloratadine in Children Using a Whole-Body Physiologically Based Pharmacokinetic Model","volume":"65","author":"Liu","year":"2025","journal-title":"J. Clin. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s40262-015-0253-7","article-title":"A physiologically based pharmacokinetic drug\u2013disease model to predict carvedilol exposure in adult and Paediatric heart failure patients by incorporating pathophysiological changes in hepatic and renal blood flows","volume":"54","author":"Rasool","year":"2015","journal-title":"Clin. Pharmacokinet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1365-2036.2009.04189.x","article-title":"metoclopramide and tardive dyskinesia","volume":"31","author":"Rao","year":"2010","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"86","DOI":"10.7326\/0003-4819-98-1-86","article-title":"Metoclopramide: Pharmacology and clinical application","volume":"98","author":"Albibi","year":"1983","journal-title":"Ann. Intern. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3700","DOI":"10.1002\/jps.21276","article-title":"Biowaiver monographs for immediate release solid oral dosage forms: Metoclopramide hydrochloride","volume":"97","author":"Stosik","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_12","unstructured":"Drug Bank (2026, March 26). Metoclopramide. Available online: https:\/\/go.drugbank.com\/drugs\/DB01233."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1124\/dmd.30.3.336","article-title":"The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6","volume":"30","author":"Desta","year":"2002","journal-title":"Drug Metab. Dispos."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/S0025-6196(11)63650-1","article-title":"Gastroesophageal reflux in infants and children","volume":"73","author":"Faubion","year":"1998","journal-title":"Mayo Clin. Proc."},{"key":"ref_15","first-page":"823","article-title":"Metoclopramide pharmacokinetics and pharmacodynamics in infants with gastroesophageal reflux","volume":"7","author":"Kearns","year":"1988","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1542\/peds.2005-2664","article-title":"Metoclopramide for the treatment of gastroesophageal reflux disease in infants: A systematic review","volume":"118","author":"Hibbs","year":"2006","journal-title":"Pediatrics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1097\/MPG.0000000000000792","article-title":"Use and safety of erythromycin and metoclopramide in hospitalized infants","volume":"61","author":"Ericson","year":"2015","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1111\/cts.12803","article-title":"Population pharmacokinetics of metoclopramide in infants, children, and adolescents","volume":"13","author":"Ge","year":"2020","journal-title":"Clin. Transl. Sci."},{"key":"ref_19","unstructured":"Drugs.com (2026, September 01). Metoclopramide. Available online: https:\/\/www.drugs.com\/metoclopramide.html."},{"key":"ref_20","unstructured":"Consulting, G. (2026, August 01). When Is a Patient a Child? Why Age Terminology Is a Regulatory Minefield. Available online: https:\/\/ganymede.consulting\/news\/patient-age-terminology-regulatory-minefield."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lokken, R.A.K., Illamola, S.M., Job, K.M., Al-Sallami, H.S., W\u2018t Jong, G., Reith, D.M., Birnbaum, A.K., and Sherwin, C.M. (2026). Advancing Pediatric Dose Scaling: Strategies, Modeling Approaches, and Clinical Applications. Pharmaceuticals, 19.","DOI":"10.3390\/ph19071090"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"959","DOI":"10.2165\/00003088-200241120-00003","article-title":"Ontogeny of hepatic and renal systemic clearance pathways in infants part I","volume":"41","author":"Alcorn","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/j.1365-2125.1991.tb05511.x","article-title":"Pharmacokinetics of metoclopramide in patients with liver cirrhosis","volume":"31","author":"Magueur","year":"1991","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/j.1552-4604.1997.tb04784.x","article-title":"Comparative Central Nervous System Effects and Pharmacokinetics of Neu-metoclopramide and Metoclopramide in Healthy Volunteers","volume":"37","author":"Rotmensch","year":"1997","journal-title":"J. Clin. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/j.1365-2125.1980.tb01064.x","article-title":"The pharmacokinetics of metoclopramide in man with observations in the dog","volume":"9","author":"Bateman","year":"1980","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1093\/ageing\/22.5.354","article-title":"The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide","volume":"22","author":"Wynne","year":"1993","journal-title":"Age Ageing"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1080\/01483919008049060","article-title":"High-performance liquid chromatographic method for the determination of metoclopramide in plasma","volume":"13","author":"Shields","year":"1990","journal-title":"J. Liq. Chromatogr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1365-2036.2009.04045.x","article-title":"Pharmacokinetic comparison of orally-disintegrating metoclopramide with conventional metoclopramide tablet formulation in healthy volunteers","volume":"30","author":"Fass","year":"2009","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.clinthera.2011.04.016","article-title":"Comparison of the Pharmacokinetics of a New 15-mg Modified-Release Tablet Formulation of Metoclopramide Versus a 10-mg Immediate-Release Tablet: A Single-and Multiple-Dose, Randomized, Open-Label, Parallel-Group Study in Healthy Mexican Male Volunteers","volume":"33","year":"2011","journal-title":"Clin. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s13318-012-0082-0","article-title":"Comparison of the pharmacokinetics of a new 30 mg modified-release tablet formulation of metoclopramide for once-a-day administration versus 10 mg immediate-release tablets: A single and multiple-dose, randomized, open-label, parallel study in healthy male subjects","volume":"37","year":"2012","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_31","first-page":"211","article-title":"Pharmacokinetic interaction study between ranitidine and metoclopramide","volume":"13","author":"Leucuta","year":"2004","journal-title":"J. Gastrointest. Liver Dis."},{"key":"ref_32","unstructured":"WHO (2026, September 02). WHO Growth Standards (0\u201324 Months). Available online: https:\/\/www.infantchart.com\/who-0-24\/."},{"key":"ref_33","unstructured":"Kane, M. (2025). CYP2D6 overview: Allele and phenotype frequencies. Medical Genetics Summaries [Internet], National Center for Biotechnology Information (US)."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1203\/00006450-198704010-00589","article-title":"Gastric Motility in Infants with Gastroesophageal Reflux (GER)","volume":"21","author":"Cannon","year":"1987","journal-title":"Pediatr. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4788","DOI":"10.18203\/2320-6012.ijrms20163766","article-title":"Liquid gastric emptying time1\/2in infants: Establishing reference range and it\u2019s co-relation with presence of gastro-esophageal reflux","volume":"4","author":"Parashar","year":"2016","journal-title":"Int. J. Res. Med. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1097\/01.rlu.0000210500.64440.76","article-title":"Relationship between gastric emptying and gastroesophageal reflux in infants and children","volume":"31","author":"Argon","year":"2006","journal-title":"Clin. Nucl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1517\/17425255.3.2.235","article-title":"Whole-body physiologically based pharmacokinetic models","volume":"3","author":"Nestorov","year":"2007","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0163-7258(96)00184-2","article-title":"Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data","volume":"73","author":"Iwatsubo","year":"1997","journal-title":"Pharmacol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/BF00644611","article-title":"Apparent volumes of distribution and drug binding to plasma proteins and tissues","volume":"13","author":"Gibaldi","year":"1978","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"523","DOI":"10.2165\/00003088-198308060-00003","article-title":"Clinical pharmacokinetics of metoclopramide","volume":"8","author":"Bateman","year":"1983","journal-title":"Clin. Pharmacokinet."},{"key":"ref_41","unstructured":"EMA (2026, August 12). Guideline on the Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation_en.pdf."},{"key":"ref_42","unstructured":"FDA (2026, August 12). PBPK Current Status and Challenges: A Regulatory Perspective, Available online: https:\/\/www.fda.gov\/media\/101469\/download."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Shahzad, I., Zamir, A., Rasool, M.F., Alali, A.S., Hussain, I., and Alqahtani, F. (2026). Development and Evaluation of Physiologically Based Pharmacokinetic (PBPK) Models to Investigate the Effect of CYP2D6 Polymorphism on Metoclopramide Systemic Exposure. Pharmaceuticals, 19.","DOI":"10.3390\/ph19071105"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S1478-5382(03)02342-4","article-title":"PK-Sim\u00ae: A physiologically based pharmacokinetic \u2018whole-body\u2019model","volume":"1","author":"Willmann","year":"2003","journal-title":"Biosilico"},{"key":"ref_45","unstructured":"FindMYSoft (2026, July 13). GetData Graph Digitizer. Available online: https:\/\/getdata-graph-digitizer.findmysoft.com\/."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cmpb.2010.01.007","article-title":"PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel","volume":"99","author":"Zhang","year":"2010","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s00280-024-04678-0","article-title":"Physiologically-based pharmacokinetic models versus allometric scaling for prediction of tyrosine-kinase inhibitor exposure from adults to children","volume":"94","author":"Centanni","year":"2024","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_48","unstructured":"PubChem (2026, September 02). Mretoclopramide, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Metoclopramide."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"183","DOI":"10.22270\/jddt.v8i6.2039","article-title":"Formulation Development to Enhance the Solubility of Metoclopramide Base Drug by Solid Dispersion and Evaluation of Transdermal Film","volume":"8","author":"Goutam","year":"2018","journal-title":"J. Drug Deliv. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1365-2125.1986.tb05201.x","article-title":"The plasma protein binding of metoclopramide in health and renal disease","volume":"21","author":"Webb","year":"1986","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2165\/00003088-198611060-00001","article-title":"Pharmacokinetics of high-dose metoclopramide in cancer patients","volume":"11","author":"McGovern","year":"1986","journal-title":"Clin. Pharmacokinet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/psp.2014.45","article-title":"Physiologically based pharmacokinetic modeling and simulation in pediatric drug development","volume":"3","author":"Maharaj","year":"2014","journal-title":"CPT Pharmacomet. Syst. Pharmacol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/9\/1482\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:06:51Z","timestamp":1789981611000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/9\/1482"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":52,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ph19091482"],"URL":"https:\/\/doi.org\/10.3390\/ph19091482","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}