{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:37:53Z","timestamp":1766050673622,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,6,30]],"date-time":"2024-06-30T00:00:00Z","timestamp":1719705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020 Operational Programme for Competitiveness and Internationalisation (PO-CI), Portugal 202","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"Portuguese funds through Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT) in the framework of projects","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"CHAIR in Onco-Innovation from Faculty of Medicine, University of Porto (FMUP)","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. Herein, we developed a popPK model for salbutamol, a short-acting \u03b22-agonist (SABA) used in asthma treatment, to identify key patient characteristics that influence treatment response. To do so, synthetic data from physiologically-based pharmacokinetic (PBPK) models was employed, followed by an external validation using real patient data derived from an equivalent study. Thirty-two virtual patients were included in this study. A two-compartment model, with first-order absorption (no delay), and linear elimination best fitted our data, according to diagnostic plots and selection criteria. External validation demonstrated a strong agreement between individual predicted and observed values. The incorporation of covariates into the basic structural model identified a significant impact of age on clearance (Cl) and intercompartmental clearance (Q); gender on Cl and the constant rate of absorption (ka); race on Cl; and weight on Cl in the volume of distribution of the peripheral compartment (V2). This study addresses critical challenges in popPK modeling, particularly data scarcity, incompleteness, and homogeneity, in traditional clinical trials, by leveraging synthetic data from PBPK modeling. Significant associations between individual characteristics and salbutamol\u2019s PK parameters, here uncovered, highlight the importance of personalized therapeutic regimens for optimal treatment outcomes.<\/jats:p>","DOI":"10.3390\/pharmaceutics16070881","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T06:04:18Z","timestamp":1719986658000},"page":"881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Toward Personalized Salbutamol Therapy: Validating Virtual Patient-Derived Population Pharmacokinetic Model with Real-World Data"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7003-4957","authenticated-orcid":false,"given":"Lara","family":"Marques","sequence":"first","affiliation":[{"name":"PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Al. Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Al. Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/978-1-0716-1554-6_17","article-title":"Sources of Interindividual Variability","volume":"2342","author":"Lin","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2174\/138920007779816002","article-title":"Pharmacokinetic and Pharmacodynamic Variability: A Daunting Challenge in Drug Therapy","volume":"8","author":"Lin","year":"2007","journal-title":"Curr. Drug Metab."},{"key":"ref_3","first-page":"10","article-title":"Developmental Changes in Pharmacokinetics and Pharmacodynamics","volume":"58","author":"Reed","year":"2018","journal-title":"Suppl. Artic. J. Clin. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1080\/10837450902891485","article-title":"Gender and Interindividual Variability in Pharmacokinetics","volume":"41","author":"Nicolas","year":"2009","journal-title":"Drug Metab. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/BF03261932","article-title":"Fundamentals of Population Pharmacokinetic Modelling","volume":"51","author":"Sherwin","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/psp4.12511","article-title":"Data Digitizing: Accurate and Precise Data Extraction for Quantitative Systems Pharmacology and Physiologically-Based Pharmacokinetic Modeling","volume":"9","author":"Wojtyniak","year":"2020","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1002\/psp4.12015","article-title":"Establishing Good Practices for Exposure\u2013Response Analysis of Clinical Endpoints in Drug Development","volume":"4","author":"Overgaard","year":"2015","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1517\/17425255.2015.1047341","article-title":"Influence of Ethnicity on Response to Asthma Drugs","volume":"11","author":"Cazzola","year":"2015","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s40262-019-00811-y","article-title":"Population Pharmacokinetics of Intravenous Salbutamol in Children with Refractory Status Asthmaticus","volume":"59","author":"Vet","year":"2020","journal-title":"Clin. Pharmacokinet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1365-2125.1996.tb00156.x","article-title":"Enantioselective Disposition of Salbutamol in Man Following Oral and Intravenous Administration","volume":"41","author":"Boulton","year":"1996","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_11","unstructured":"(2022, October 07). Salbutamol: Uses, Interactions, Mechanism of Action|DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB01001."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"443","DOI":"10.5603\/ARM.a2020.0132","article-title":"Short-Acting Inhaled B2-Agonists: Why, Whom, What, How?","volume":"88","author":"Emeryk","year":"2020","journal-title":"Adv. Respir. Med."},{"key":"ref_13","unstructured":"Kim, J.S., and Story, R.E. (2021). Bronchodilators. Allergy and Asthma: Practical Diagnosis and Management: Second Edition, StatPearls Publishing."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s002040050059","article-title":"A Review of the Toxicology of Salbutamol (Albuterol)","volume":"68","author":"Libretto","year":"1994","journal-title":"Arch. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"77","DOI":"10.2165\/00003495-198938010-00004","article-title":"Salbutamol in the 1980s: A Reappraisal of Its Clinical Efficacy","volume":"38","author":"Price","year":"1989","journal-title":"Drugs"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1165\/rcmb.2017-0315LE","article-title":"B2-Agonists Enhance Asthma-Relevant Inflammatory Mediators in Human Airway Epithelial Cells","volume":"58","author":"Ritchie","year":"2018","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1183\/13993003.02223-2018","article-title":"Is It Time to Move Away from Short-Acting Beta-Agonists in Asthma Management?","volume":"53","author":"Martin","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1053\/rmed.2000.0820","article-title":"Bronchodilator Tolerance and Rebound Bronchoconstriction during Regular Inhaled \u03b2-Agonist Treatment","volume":"94","author":"Hancox","year":"2000","journal-title":"Respir. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1164\/ajrccm.156.6.96-08042","article-title":"Effect of Regular Inhaled Albuterol on Allergen-Induced Late Responses and Sputum Eosinophils in Asthmatic Subjects","volume":"156","author":"Gauvreau","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/0140-6736(93)92695-P","article-title":"Regular Inhaled Salbutamol and Airway Responsiveness to Allergen","volume":"342","author":"Cockcroft","year":"1993","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1901046","DOI":"10.1183\/13993003.01046-2019","article-title":"GINA 2019: A Fundamental Change in Asthma Management: Treatment of Asthma with Short-Acting Bronchodilators Alone Is No Longer Recommended for Adults and Adolescents","volume":"53","author":"Reddel","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_22","unstructured":"(2022, November 04). AstraZeneca SABINA Programme Demonstrates SABA Reliever Overuse Is a Global Issue in Asthma Management. Available online: https:\/\/www.astrazeneca.com\/media-centre\/medical-releases\/sabina-programme-demonstrates-saba-reliever-overuse-is-a-global-issue-in-asthma-management.html."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1093\/fampra\/cmab013","article-title":"Over-Prescription of Short-Acting Beta Agonists in the Treatment of Asthma","volume":"38","author":"Werkhoven","year":"2021","journal-title":"Fam. Pract."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100862","DOI":"10.1016\/j.imu.2022.100862","article-title":"A Contemporary Review on the Important Role of In Silico Approaches for Managing Different Aspects of COVID-19 Crisis","volume":"28","author":"Moradi","year":"2022","journal-title":"Inform. Med. Unlocked"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-1-0716-3449-3_4","article-title":"In Silico Clinical Trials: Is It Possible?","volume":"2716","author":"Tixier","year":"2024","journal-title":"Methods Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1093\/bib\/bby043","article-title":"In Silico Clinical Trials: Concepts and Early Adoptions","volume":"20","author":"Pappalardo","year":"2019","journal-title":"Brief. Bioinform."},{"key":"ref_27","unstructured":"(2024, March 22). Modelling and Simulation: Questions and Answers|European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/human-regulatory-overview\/research-and-development\/scientific-guidelines\/clinical-pharmacology-and-pharmacokinetics\/modelling-and-simulation-questions-and-answers."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1002\/psp4.12708","article-title":"Scientific and Regulatory Evaluation of Empirical Pharmacometric Models: An Application of the Risk Informed Credibility Assessment Framework","volume":"10","author":"Musuamba","year":"2021","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_29","unstructured":"(2024, March 23). Population Pharmacokinetics|FDA, Available online: http:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-dolcuments\/population-pharmacokinetics."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e38","DOI":"10.1038\/psp.2013.14","article-title":"Basic Concepts in Population Modeling, Simulation, and Model-Based Drug Development\u2014Part 2: Introduction to Pharmacokinetic Modeling Methods","volume":"2","author":"Mould","year":"2013","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.2174\/1381612822666160128150005","article-title":"Pharmacokinetic Considerations of Inhaled Pharmaceuticals for Systemic Delivery","volume":"22","author":"Hu","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/psp4.12611","article-title":"Approaches to Handling Missing or \u201cProblematic\u201d Pharmacology Data: Pharmacokinetics","volume":"10","author":"Irby","year":"2021","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"O\u2019Hara, K., Martin, J.H., and Schneider, J.J. (2020). Barriers and Challenges in Performing Pharmacokinetic Studies to Inform Dosing in the Neonatal Population. Pharmacy, 8.","DOI":"10.3390\/pharmacy8010016"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1002\/psp4.12374","article-title":"Handling Missing Dosing History in Population Pharmacokinetic Modeling: An Extension to MDM Method","volume":"8","author":"Wang","year":"2019","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Marques, L., and Vale, N. (2022). Salbutamol in the Management of Asthma: A Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232214207"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Shamsuddin, R., Maweu, B.M., Li, M., and Prabhakaran, B. (2018, January 4\u20137). Virtual Patient Model: An Approach for Generating Synthetic Healthcare Time Series Data. Proceedings of the 2018 IEEE International Conference on Healthcare Informatics (ICHI), New York, NY, USA.","DOI":"10.1109\/ICHI.2018.00031"},{"key":"ref_37","first-page":"1","article-title":"Synthetic Data Generation by Artificial Intelligence to Accelerate Research and Precision Medicine in Hematology","volume":"7","author":"Sala","year":"2023","journal-title":"JCO Clin. Cancer Inform."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/s41746-023-00927-3","article-title":"Harnessing the Power of Synthetic Data in Healthcare: Innovation, Application, and Privacy","volume":"6","author":"Shung","year":"2023","journal-title":"Npj Digit. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e2300045","DOI":"10.1200\/CCI.23.00045","article-title":"Opportunities and Challenges of Synthetic Data Generation in Oncology","volume":"7","author":"Jacobs","year":"2023","journal-title":"JCO Clin. Cancer Inform."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41591-022-02160-z","article-title":"The next Generation of Evidence-Based Medicine","volume":"29","author":"Subbiah","year":"2023","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41572-021-00316-8","article-title":"Improving Diversity in Medical Research","volume":"7","author":"Sharma","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1136\/bmjebm-2018-111115","article-title":"Inclusion and Exclusion Criteria and the Problem of Describing Homogeneity of Study Populations in Clinical Trials","volume":"24","author":"Porzsolt","year":"2019","journal-title":"BMJ Evid.-Based Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4103\/0972-2327.173308","article-title":"Homogeneity and the Outcome of Clinical Trials: An Appraisal of the Outcome of Recent Clinical Trials on Endovascular Intervention in Acute Ischemic Stroke","volume":"19","author":"Husain","year":"2016","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"365","DOI":"10.4103\/0972-2327.143984","article-title":"Influence of Trial Design, Heterogeneity and Regulatory Environment on the Results of Clinical Trials: An Appraisal in the Context of Recent Trials on Acute Stroke Intervention","volume":"17","author":"Srijithesh","year":"2014","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/bcp.12267","article-title":"Paediatric Pharmacokinetics: Key Considerations","volume":"79","author":"Batchelor","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_46","unstructured":"(2024, March 23). Salbutamol-Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Renal Dose, Hepatic Dose|Drug Index|Pediatric Oncall. Available online: https:\/\/www.pediatriconcall.com\/drugs\/salbutamol\/934."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1021\/mp200620m","article-title":"Deposition, Diffusion and Transport Mechanism of Dry Powder Microparticulate Salbutamol, at the Respiratory Epithelia","volume":"9","author":"Haghi","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1046\/j.1365-2125.1996.00493.x","article-title":"Pharmacokinetics of Inhaled Drugs","volume":"42","author":"Lipworth","year":"1996","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_49","unstructured":"U.S. Food & Drug Administration (2024, March 23). 2015\u20132019 Drug Trials Snapshots Summary Report, Available online: https:\/\/www.fda.gov\/media\/143592\/download."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1046\/j.1365-2125.2003.02007.x","article-title":"Age-Related Changes in Pharmacokinetics and Pharmacodynamics: Basic Principles and Practical Applications","volume":"57","author":"Mangoni","year":"2004","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/sj.mn.7800206","article-title":"Impairment of Hepatic Microcirculation in Fatty Liver","volume":"10","author":"Ijaz","year":"2003","journal-title":"Microcirculation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2165\/11318100-000000000-00000","article-title":"Effect of Obesity on the Pharmacokinetics of Drugs in Humans","volume":"49","author":"Hanley","year":"2010","journal-title":"Clin. Pharmacokinet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"277","DOI":"10.2165\/11599410-000000000-00000","article-title":"Impact of Obesity on Drug Metabolism and Elimination in Adults and Children","volume":"51","author":"Brill","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0074-7742(08)00001-9","article-title":"Gender Differences in Pharmacological Response","volume":"83","author":"Anderson","year":"2008","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e00890","DOI":"10.1002\/prp2.890","article-title":"Inter-Ethnic Differences in Pharmacokinetics\u2014Is There More That Unites than Divides?","volume":"9","author":"Olafuyi","year":"2021","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1124\/pr.111.004580","article-title":"Pharmacology and Therapeutics of Bronchodilators","volume":"64","author":"Cazzola","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1111\/j.1365-2222.2011.03696.x","article-title":"Pharmacogenetics of \u03922 Adrenergic Receptor Gene Polymorphisms, Long-Acting \u03b2-Agonists and Asthma","volume":"41","author":"Chung","year":"2011","journal-title":"Clin. Exp. Allergy"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/7\/881\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:08:04Z","timestamp":1760108884000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/7\/881"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,30]]},"references-count":57,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["pharmaceutics16070881"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16070881","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2024,6,30]]}}}