{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:06:39Z","timestamp":1785391599189,"version":"3.55.0"},"reference-count":29,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013209","name":"Hellenic Foundation for Research and Innovation","doi-asserted-by":"publisher","award":["1058"],"award-info":[{"award-number":["1058"]}],"id":[{"id":"10.13039\/501100013209","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Objectives: Tacrolimus, a Biopharmaceutics Classification System (BCS) class II drug, is widely used for transplant patients to prevent graft rejection. To enhance its bioavailability, amorphous solid dispersion (ASD) formulations were developed and evaluated. The release properties of several ASD-based tacrolimus formulations were studied using an in-house USP IV dissolution method. Methods: The pharmacokinetics of a promising test product were compared with the commercially available Advagraf\u00ae in a pilot clinical bioequivalence study with 12 healthy subjects. A previously published PBPK model for tacrolimus was validated using in vivo data and then applied to predict the human pharmacokinetics of several ASD-based tacrolimus formulations. Results: This study compares the pharmacokinetic (PK) parameters\u2014AUC, Cmax, and Tmax\u2014of Advagraf\u00ae and a test formulation using two methodologies: one incorporating the dissolution profile directly into the PBPK model and the other utilizing the DLM approach. The results show that both methods provided accurate predictions for Cmax and Tmax, with the dissolution profile approach underestimating AUC slightly, while the DLM method predicted AUC adequately. Sensitivity analysis refining the DLM scalars in the Ileum and Colon led to optimized predictions of PK parameters. Furthermore, this study explores the use of PBPK modeling to predict in vivo behavior for additional tacrolimus formulations, highlighting the influence of formulation composition, such as the inclusion of Eudragit-S100, on dissolution profiles and bioavailability. Conclusions: This study evaluates formulations with different compositions and manufacturing characteristics; key factors that could influence their performance in the body were identified. These insights\u2014spanning qualitative, quantitative, and manufacturing aspects\u2014can greatly simplify the development of generic drugs, offering strong evidence of the critical role that physiologically based pharmacokinetic (PBPK) modeling can play in the early phases of generic drug development, especially in designing and assessing biopredictive dissolution methods.<\/jats:p>","DOI":"10.3390\/pharmaceutics17020227","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T05:53:22Z","timestamp":1739166802000},"page":"227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Integrating In Vitro Dissolution and Physiologically Based Pharmacokinetic Modeling for Generic Drug Development: Evaluation of Amorphous Solid Dispersion Formulations for Tacrolimus"],"prefix":"10.3390","volume":"17","author":[{"given":"Evangelos","family":"Karakitsios","sequence":"first","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Faidra-Galini","family":"Angelerou","sequence":"additional","affiliation":[{"name":"Pharmathen SA, 15125 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iasonas","family":"Kapralos","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Tsakiridou","sequence":"additional","affiliation":[{"name":"Pharmathen SA, 15125 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lida","family":"Kalantzi","sequence":"additional","affiliation":[{"name":"Pharmathen SA, 15125 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5087-4003","authenticated-orcid":false,"given":"Aristides","family":"Dokoumetzidis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ejpb.2018.05.024","article-title":"Use of Biorelevant Dissolution and PBPK Modeling to Predict Oral Drug Absorption","volume":"129","author":"Kaur","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18","DOI":"10.14227\/DT260319P18","article-title":"Physiologically Based Pharmacokinetic (PBPK) Modelling for In Vitro-In Vivo Extrapolation: Emphasis on the Use of Dissolution Data","volume":"26","author":"Ghate","year":"2019","journal-title":"Dissolution Technol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105618","DOI":"10.1016\/j.ejps.2020.105618","article-title":"In Silico Prediction of Bioequivalence of Isosorbide Mononitrate Tablets with Different Dissolution Profiles Using PBPK Modeling and Simulation","volume":"157","author":"Zhang","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejpb.2020.03.012","article-title":"Establishment of a Clinically Relevant Specification for Dissolution Testing Using Physiologically Based Pharmacokinetic (PBPK) Modeling Approaches","volume":"151","author":"Kato","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ejps.2019.05.013","article-title":"PBPK Modeling Coupled with Biorelevant Dissolution to Forecast the Oral Performance of Amorphous Solid Dispersion Formulations","volume":"135","author":"Kambayashi","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1080\/03639045.2019.1648502","article-title":"Evaluating the Bioequivalence of Metronidazole Tablets and Analyzing the Effect of in Vitro Dissolution on in Vivo Absorption Based on PBPK Modeling","volume":"45","author":"Zhang","year":"2019","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1208\/s12249-020-01643-x","article-title":"Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling","volume":"21","author":"Kaur","year":"2020","journal-title":"AAPS PharmSciTech"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105750","DOI":"10.1016\/j.ejps.2021.105750","article-title":"Evaluating the Impact of Acid-Reducing Agents on Drug Absorption Using Biorelevant in Vitro Tools and PBPK Modeling\u2014Case Example Dipyridamole","volume":"160","author":"Segregur","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.3109\/03639045.2014.991399","article-title":"Prediction of in Vivo Drug Performance Using in Vitro Dissolution Coupled with STELLA: A Study with Selected Drug Products","volume":"41","author":"Chakraborty","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1016\/j.xphs.2017.12.024","article-title":"Investigating the Impact of Drug Crystallinity in Amorphous Tacrolimus Capsules on Pharmacokinetics and Bioequivalence Using Discriminatory In Vitro Dissolution Testing and Physiologically Based Pharmacokinetic Modeling and Simulation","volume":"107","author":"Purohit","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.jconrel.2020.11.055","article-title":"Predicting Drug Release and Degradation Kinetics of Long-Acting Microsphere Formulations of Tacrolimus for Subcutaneous Injection","volume":"329","author":"Gao","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1124\/dmd.111.039248","article-title":"Physiologically Based Pharmacokinetic Modeling of Intestinal First-Pass Metabolism of CYP3A Substrates with High Intestinal Extraction","volume":"39","author":"Gertz","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Pei, L., Li, R., Zhou, H., Du, W., Gu, Y., Jiang, Y., Wang, Y., Chen, X., Sun, J., and Zhu, J. (2023). A Physiologically Based Pharmacokinetic Approach to Recommend an Individual Dose of Tacrolimus in Adult Heart Transplant Recipients. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15112580"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/psp4.12392","article-title":"A Theoretical Physiologically-Based Pharmacokinetic Approach to Ascertain Covariates Explaining the Large Interpatient Variability in Tacrolimus Disposition","volume":"8","author":"Emoto","year":"2019","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Van Der Veken, M., Brouwers, J., Ozbey, A.C., Umehara, K., Stillhart, C., Knops, N., Augustijns, P., and Parrott, N.J. (2023). Investigating Tacrolimus Disposition in Paediatric Patients with a Physiologically Based Pharmacokinetic Model Incorporating CYP3A4 Ontogeny, Mechanistic Absorption and Red Blood Cell Binding. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15092231"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"He, Q., Bu, F., Wang, Q., Li, M., Lin, J., Tang, Z., Mak, W.Y., Zhuang, X., Zhu, X., and Lin, H.-S. (2022). Examination of the Impact of CYP3A4\/5 on Drug\u2013Drug Interaction between Schizandrol A\/Schizandrol B and Tacrolimus (FK-506): A Physiologically Based Pharmacokinetic Modeling Approach. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094485"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102990","DOI":"10.1016\/j.jddst.2021.102990","article-title":"On the Usefulness of Four in Vitro Methodologies in Screening for Product Related Differences in Tacrolimus Exposure after Oral Administration of Amorphous Solid Dispersions with Modified Release Characteristics in the Fasted State","volume":"69","author":"Tsakiridou","year":"2022","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Tsakiridou, G., Reppas, C., Kuentz, M., and Kalantzi, L. (2019). A Novel Rheological Method to Assess Drug-Polymer Interactions Regarding Miscibility and Crystallization of Drug in Amorphous Solid Dispersions for Oral Drug Delivery. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11120625"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ejpb.2015.03.009","article-title":"In-Vitro Simulation of Luminal Conditions for Evaluation of Performance of Oral Drug Products: Choosing the Appropriate Test Media","volume":"93","author":"Markopoulos","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ejpb.2020.08.025","article-title":"Dissolution Testing of Modified Release Products with Biorelevant Media: An OrBiTo Ring Study Using the USP Apparatus III and IV","volume":"156","author":"Reppas","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_21","first-page":"100834","article-title":"Advances in the Development of Amorphous Solid Dispersions: The Role of Polymeric Carriers","volume":"18","author":"Zhang","year":"2023","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1021\/acs.molpharmaceut.1c00972","article-title":"Investigating the Potential of Ethyl Cellulose and a Porosity-Increasing Agent as a Carrier System for the Formulation of Amorphous Solid Dispersions","volume":"19","author":"Everaerts","year":"2022","journal-title":"Mol. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.jddst.2017.06.010","article-title":"Application of Surfactants in Solid Dispersion Technology for Improving Solubility of Poorly Water Soluble Drugs","volume":"41","author":"Chaudhari","year":"2017","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ejps.2006.04.016","article-title":"Formulation of Poorly Water-Soluble Drugs for Oral Administration: Physicochemical and Physiological Issues and the Lipid Formulation Classification System","volume":"29","author":"Pouton","year":"2006","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0009-9236(95)90153-1","article-title":"Pharmacokinetics of Tacrolimus in Liver Transplant Patients*","volume":"57","author":"Jusko","year":"1995","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S1056-8719(02)00158-2","article-title":"Validation of Methods to Study the Distribution and Protein Binding of Tacrolimus in Human Blood","volume":"46","author":"Zahir","year":"2001","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/jps.10041","article-title":"Tacrolimus Is a Class II Low-Solubility High-Permeability Drug: The Effect of P-Glycoprotein Efflux on Regional Permeability of Tacrolimus in Rats","volume":"91","author":"Tamura","year":"2002","journal-title":"J. Pharm. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1177\/00912700122010519","article-title":"Comparative Tacrolimus Pharmacokinetics: Normal versus Mildly Hepatically Impaired Subjects","volume":"41","author":"Bekersky","year":"2001","journal-title":"J. Clin. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1124\/dmd.105.008680","article-title":"Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro","volume":"34","author":"Dai","year":"2006","journal-title":"Drug Metab. Dispos."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/2\/227\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:30:22Z","timestamp":1760027422000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/2\/227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,10]]},"references-count":29,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["pharmaceutics17020227"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17020227","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,10]]}}}