{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:01:30Z","timestamp":1790017290812,"version":"4.0.1"},"reference-count":54,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and ICT, MSIT","award":["RS-2022-00155857"],"award-info":[{"award-number":["RS-2022-00155857"]}]},{"name":"Korea government","award":["RS-2023-00278597"],"award-info":[{"award-number":["RS-2023-00278597"]}]},{"name":"Korea government","award":["RS-2022-NR069643"],"award-info":[{"award-number":["RS-2022-NR069643"]}]},{"name":"Korea government","award":["RS-2022-NR070856"],"award-info":[{"award-number":["RS-2022-NR070856"]}]},{"name":"Korea Ministry of Environment","award":["RS-2021-KE001333"],"award-info":[{"award-number":["RS-2021-KE001333"]}]},{"name":"Ministry of Health & Welfare and MSIT","award":["RS-2024-00460694"],"award-info":[{"award-number":["RS-2024-00460694"]}]},{"name":"Korea Institute of Toxicology (KIT) Research Program","award":["2710008763"],"award-info":[{"award-number":["2710008763"]}]},{"name":"Korea Institute of Toxicology (KIT) Research Program","award":["KK-2401-01"],"award-info":[{"award-number":["KK-2401-01"]}]},{"name":"Ministry of Health & Welfare, Republic of Korea","award":["RS-2024-00336984"],"award-info":[{"award-number":["RS-2024-00336984"]}]},{"name":"Ministry of Health & Welfare, Republic of Korea","award":["RS-2025-02306055"],"award-info":[{"award-number":["RS-2025-02306055"]}]},{"DOI":"10.13039\/501100003052","name":"Ministry of Trade, Industry, and Energy","doi-asserted-by":"crossref","award":["RS-2024-00434342"],"award-info":[{"award-number":["RS-2024-00434342"]}],"id":[{"id":"10.13039\/501100003052","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background and Objective: Tofacitinib (TOF), an oral Janus kinase inhibitor used to treat rheumatoid arthritis (RA), is extensively metabolized by cytochrome P450 (CYP) 3A4. Ritonavir (RTV), a protease inhibitor, is commonly used as a pharmacokinetic (PK) enhancer due to its potent CYP3A4 inhibitory effects. Considering the prevalence of comorbidities in RA patients, it is possible to use TOF and RTV concurrently, raising concerns about potential drug\u2013drug interactions (DDIs). The current study aims to assess the potential DDIs between RTV and TOF. Methods: An in vivo rat study was conducted to investigate the impacts of RTV on the PK of TOF. Rats were randomly divided into three groups: vehicle, RTV 10 mg\/kg, and RTV 20 mg\/kg, each undergoing four days of pretreatment. On the test day, TOF (10 mg\/kg) was administered following co-administration of the respective RTV doses. Blood samples were collected at the pre-specified time points. Plasma concentrations of TOF were quantified using liquid chromatography coupled with mass spectrometry, and PK parameters were analyzed using non-compartmental analysis. Results: RTV (10 and 20 mg\/kg) increased the area under the curve of TOF by 2.53-fold (95% CI: 1.64\u20133.43) and 5.39-fold (95% CI: 4.47\u20136.33), respectively, and the maximum concentration by 1.47-fold (95% CI: 0.99\u20132.00) and 2.86-fold (95% CI: 2.39\u20133.37), respectively. Whereas the half-life (t1\/2) remained unchanged. Conclusions: RTV substantially increased TOF exposure in rats. These results suggest the need for dose adjustments of TOF during co-administration with RTV in clinical settings. Further clinical research is needed to confirm these findings.<\/jats:p>","DOI":"10.3390\/ph18101561","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T16:33:22Z","timestamp":1760632402000},"page":"1561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Effects of Ritonavir on the Pharmacokinetics of Tofacitinib in Rats"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-1266","authenticated-orcid":false,"given":"Sung-yoon","family":"Yang","sequence":"first","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1609-2010","authenticated-orcid":false,"given":"Hyunjung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Bio-AI Convergence, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3257-5215","authenticated-orcid":false,"given":"Tham Thi","family":"Bui","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea"},{"name":"Faculty of Pharmacy, Haiphong University of Medicine and Pharmacy, Haiphong 04212, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-0957","authenticated-orcid":false,"given":"Quyen Thi","family":"Tran","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, PHENIKAA University, Yen Nghia, Ha Dong, Hanoi 12116, Vietnam"},{"name":"A&A Green Phoenix Group JSC, PHENIKAA Research and Technology Institute (PRATI), No. 167 Hoang Ngan, Trung Hoa, Cau Giay, Hanoi 11313, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0577-4983","authenticated-orcid":false,"given":"Lien Thi","family":"Ngo","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, PHENIKAA University, Yen Nghia, Ha Dong, Hanoi 12116, Vietnam"},{"name":"A&A Green Phoenix Group JSC, PHENIKAA Research and Technology Institute (PRATI), No. 167 Hoang Ngan, Trung Hoa, Cau Giay, Hanoi 11313, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8793-2449","authenticated-orcid":false,"given":"Hwi-yeol","family":"Yun","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea"},{"name":"Department of Bio-AI Convergence, Chungnam National University, Daejeon 34134, Republic of Korea"},{"name":"Senior Health Convergence Research Center, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3531-0618","authenticated-orcid":false,"given":"Sangkeun","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Bio-AI Convergence, Chungnam National University, Daejeon 34134, Republic of Korea"},{"name":"Department of Computer Science and Engineering, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6026-7063","authenticated-orcid":false,"given":"Jung-woo","family":"Chae","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea"},{"name":"Department of Bio-AI Convergence, Chungnam National University, Daejeon 34134, Republic of Korea"},{"name":"Senior Health Convergence Research Center, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1476-9255-7-41","article-title":"Anti-inflammatory activity and neutrophil reductions mediated by the JAK1\/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis","volume":"7","author":"Meyer","year":"2010","journal-title":"J. Inflamm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2147\/PTT.S161453","article-title":"Tofacitinib in the management of active psoriatic arthritis: Patient selection and perspectives","volume":"9","author":"Ly","year":"2019","journal-title":"Psoriasis Targets Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1756284819848631","DOI":"10.1177\/1756284819848631","article-title":"Tofacitinib in the treatment of ulcerative colitis: Efficacy and safety from clinical trials to real-world experience","volume":"12","author":"Parigi","year":"2019","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/cpdd.171","article-title":"Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers","volume":"4","author":"Krishnaswami","year":"2015","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1124\/dmd.113.054940","article-title":"The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans","volume":"42","author":"Dowty","year":"2014","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_6","unstructured":"U.S. Food and Drug Administration (2025, September 05). Pharmacology Review(s): Tofacitinib (NDA 203214Orig1s000), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2012\/203214Orig1s000PharmR.pdf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/cpdd.71","article-title":"Evaluation of the effect of fluconazole and ketoconazole on the pharmacokinetics of tofacitinib in healthy adult subjects","volume":"3","author":"Gupta","year":"2014","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Loos, N.H.C., Beijnen, J.H., and Schinkel, A.H. (2023). The inhibitory and inducing effects of ritonavir on hepatic and intestinal CYP3A and other drug-handling proteins. Biomed. Pharmacother., 162.","DOI":"10.1016\/j.biopha.2023.114636"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"375","DOI":"10.3109\/07853890.2011.572905","article-title":"Ritonavir-boosted protease inhibitors in HIV therapy","volume":"43","author":"Hull","year":"2011","journal-title":"Ann. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7532","DOI":"10.1128\/JVI.72.9.7532-7541.1998","article-title":"In Vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor","volume":"72","author":"Carrillo","year":"1998","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"310","DOI":"10.2174\/138920008784220664","article-title":"Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4","volume":"9","author":"Zhou","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1053\/j.ajkd.2009.01.268","article-title":"Drug-drug interaction in a kidney transplant recipient receiving HIV salvage therapy and tacrolimus","volume":"54","author":"Mertz","year":"2009","journal-title":"Am. J. Kidney Dis. Off. J. Natl. Kidney Found."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1007\/s00228-010-0879-1","article-title":"Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir\/ritonavir","volume":"66","author":"Nieminen","year":"2010","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1128\/AAC.00526-07","article-title":"Steady-state pharmacokinetic and safety profiles of voriconazole and ritonavir in healthy male subjects","volume":"51","author":"Liu","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"ref_15","unstructured":"World Health Organization (2025, October 10). Rheumatoid Arthritis. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/rheumatoid-arthritis."},{"key":"ref_16","unstructured":"CDC (2025, October 10). IBD Facts and Stats. Inflamm. Bowel Dis, Available online: https:\/\/www.cdc.gov\/inflammatory-bowel-disease\/php\/facts-stats\/index.html."},{"key":"ref_17","unstructured":"UNAIDS (2025, October 10). Global HIV & AIDS Statistics\u2014Fact Sheet | UNAIDS. Available online: https:\/\/www.unaids.org\/en\/resources\/fact-sheet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1177\/0897190019869158","article-title":"High Levels of Polypharmacy in Rheumatoid Arthritis-A Challenge Not Covered by Current Management Recommendations: Data from a Large Real-Life Study","volume":"34","author":"Gomides","year":"2021","journal-title":"J. Pharm. Pract."},{"key":"ref_19","first-page":"51","article-title":"Rheumatoid arthritis in patients with HIV: Management challenges","volume":"8","author":"Carroll","year":"2016","journal-title":"Open Access Rheumatol. Res. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1056\/NEJMoa2109927","article-title":"Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis","volume":"386","author":"Ytterberg","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Loos, N.H.C., Beijnen, J.H., and Schinkel, A.H. (2022). The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179866"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/bdd.1855","article-title":"Assessment of CYP3A-mediated drug-drug interaction potential for victim drugs using an in vivo rat model","volume":"34","author":"Rioux","year":"2013","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1124\/dmd.110.037523","article-title":"Complex drug interactions of HIV protease inhibitors 1: Inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir","volume":"39","author":"Kirby","year":"2011","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, J.-S., Kim, H.-S., Jung, Y.-S., Choi, H.-G., and Kim, S.-H. (2021). Pharmacokinetic Drug Interaction between Tofacitinib and Voriconazole in Rats. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13050740"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/S0090-9556(25)07487-2","article-title":"Inhibition and kinetics of cytochrome P4503A activity in microsomes from rat, human, and cdna-expressed human cytochrome P450","volume":"24","author":"Ghosal","year":"1996","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/bcp.12668","article-title":"Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies","volume":"80","author":"Greenblatt","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","unstructured":"Center for Drug Evaluation and Research, and Food and Drug Administration (2012). Pharmacology Review(s) of Tofacitinib, Center for Drug Evaluation and Research, Food and Drug Administration."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e02283-16","DOI":"10.1128\/AAC.02283-16","article-title":"Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques","volume":"61","author":"Venuto","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Liu, P., Wu, S., and Dong, Z. (2021). Identification of the metabolites of tofacitinib in liver microsomes by liquid chromatography combined with high resolution mass spectrometry. Biomed. Chromatogr., 35.","DOI":"10.1002\/bmc.5081"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lewis, D.F.V. (1996). Cytochromes P450: Structure, Function and Mechanism, Taylor & Francis.","DOI":"10.1201\/9781482272772"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Jiang, F., Zhang, C., Lu, Z., Liu, J., Liu, P., Huang, M., and Zhong, G. (2022). Simultaneous absolute protein quantification of seven cytochrome P450 isoforms in rat liver microsomes by LC-MS\/MS-based isotope internal standard method. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.906027"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1124\/dmd.122.000915","article-title":"Sexual Dimorphism in the Expression of Cytochrome P450 Enzymes in Rat Heart, Liver, Kidney, Lung, Brain, and Small Intestine","volume":"51","author":"Gerges","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"ref_33","unstructured":"Park, M.-Y. (2018). Effects of Cytochrome P450 (CYP) Inducers and Inhibitors on Tofacitinib Pharmacokinetics in Rats. [Master\u2019s Thesis, Ajou University]."},{"key":"ref_34","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_35","first-page":"552","article-title":"Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4\/3A5: Mechanism-based inactivation of cytochrome P4503A by ritonavir","volume":"26","author":"Koudriakova","year":"1998","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1097\/00004714-199908000-00001","article-title":"Extensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: The clinical dilemma of concurrent inhibition and induction","volume":"19","author":"Greenblatt","year":"1999","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1111\/j.1365-2125.2009.03545.x","article-title":"Inhibition of oral midazolam clearance by boosting doses of ritonavir, and by 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an experimental catalytic mimic of glutathione oxidase","volume":"68","author":"Greenblatt","year":"2009","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/clpt.2011.164","article-title":"Determining the time course of CYP3A inhibition by potent reversible and irreversible CYP3A inhibitors using A limited sampling strategy","volume":"90","author":"Katzenmaier","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.clpt.2005.11.009","article-title":"Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: Comparison with ritonavir","volume":"79","author":"Culmmerdek","year":"2006","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/00042560-200006010-00007","article-title":"Differential impairment of triazolam and zolpidem clearance by ritonavir","volume":"24","author":"Greenblatt","year":"2000","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lee, J.S., and Kim, S.H. (2019). Dose-Dependent Pharmacokinetics of Tofacitinib in Rats: Influence of Hepatic and Intestinal First-Pass Metabolism. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11070318"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s40005-020-00490-z","article-title":"Simple determination and quantification of tofacitinib, a JAK inhibitor, in rat plasma, urine and tissue homogenates by HPLC and its application to a pharmacokinetic study","volume":"50","author":"Kim","year":"2020","journal-title":"J. Pharm. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"361","DOI":"10.4062\/biomolther.2020.006","article-title":"Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats","volume":"28","author":"Gwak","year":"2020","journal-title":"Biomol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"510","DOI":"10.4062\/biomolther.2022.049","article-title":"Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats","volume":"30","author":"Bae","year":"2022","journal-title":"Biomol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1080\/13880209.2020.1738504","article-title":"Effects of naringenin on the pharmacokinetics of tofacitinib in rats","volume":"58","author":"Wang","year":"2020","journal-title":"Pharm. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/cpdd.741","article-title":"Phase 1 Dose-Escalation Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Tofacitinib in Japanese Healthy Volunteers","volume":"9","author":"Miyoshi","year":"2020","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ejpb.2005.03.008","article-title":"Use of nonlinear mixed effect modeling for the intestinal absorption data: Application to ritonavir in the rat","volume":"61","year":"2005","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s11095-004-9004-4","article-title":"Predicting Drug Disposition via Application of BCS: Transport\/Absorption\/Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System","volume":"22","author":"Wu","year":"2005","journal-title":"Pharm. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/bcp.14994","article-title":"Clinical evaluation of the potential drug\u2013drug interactions of savolitinib: Interaction with rifampicin, itraconazole, famotidine or midazolam","volume":"88","author":"Ren","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1002\/psp4.12449","article-title":"Recommendations for the Design of Clinical Drug-Drug Interaction Studies With Itraconazole Using a Mechanistic Physiologically-Based Pharmacokinetic Model","volume":"8","author":"Chen","year":"2019","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Yu, J., Rioux, N., Gardner, I., Owens, K., and Ragueneau-Majlessi, I. (2024). Metabolite Measurement in Index Substrate Drug Interaction Studies: A Review of the Literature and Recent New Drug Application Reviews. Metabolites, 14.","DOI":"10.3390\/metabo14100522"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1124\/dmd.117.078691","article-title":"Risk of Clinically Relevant Pharmacokinetic-Based Drug-Drug Interactions with Drugs Approved by the U.S. Food and Drug Administration Between 2013 and 2016","volume":"46","author":"Yu","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"ref_53","unstructured":"European Medicines Agency (2025, September 14). Guideline on Bioanalytical Method Validation. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-bioanalytical-method-validation_en.pdf."},{"key":"ref_54","unstructured":"U.S. Department of Health and Human Services, Food and Drug Administration (2025, September 14). Bioanalytical Method Validation Guidance for Industry. Biopharmaceutics, Available online: https:\/\/www.fda.gov\/files\/drugs\/published\/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/10\/1561\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T04:37:21Z","timestamp":1760762241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/10\/1561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ph18101561"],"URL":"https:\/\/doi.org\/10.3390\/ph18101561","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]}}}