{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:25:45Z","timestamp":1787199945766,"version":"build-2736575974"},"reference-count":58,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    pH\u2010dependent drug\u2013drug interactions (DDIs) commonly occur when acid\u2010reducing agents (ARAs) are co\u2010administered with weakly basic drugs. Although physiologically based pharmacokinetic (PBPK) modeling effectively evaluates such DDIs, its use is limited by reliance on costly commercial software. This study developed a PBPK\u2010informed machine learning model to support early assessment of pH\u2010dependent DDI risk in drug development. PBPK models were built for 14 representative weakly basic drugs using literature\u2010derived parameters to identify eight key determinants (e.g., solubility and pKa). Based on these distributions, virtual drugs were generated and simulated under varying gastric pH conditions; compounds with DDI AUC ratios &lt;\u20090.1 were excluded, yielding 4339 virtual drugs. An extreme gradient boosting (XGBoost) algorithm was used to develop the machine learning model, and an external validation set comprising clinically observed data from an additional eight drugs was employed. The XGBoost model showed excellent internal performance (training:\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20091.00, MAPE\u2009=\u20090.99; test:\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.98, MAPE\u2009=\u20092.64). When evaluated using an external validation set comprising clinically observed data from eight drugs, 100% of the predicted values fell within the 0.5\u20132.0\u2010fold range of the observed clinical values. For DDI AUC risk classification, the XGBoost model achieved an accuracy of 87.5% (7\/8). This PBPK\u2010informed ML framework enables efficient screening of pH\u2010dependent DDI risk for weakly basic drugs co\u2010administered with ARAs. The freely accessible web tool (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/ddi-antacid.xy3yx.com\/\">https:\/\/ddi\u2010antacid.xy3yx.com\/<\/jats:ext-link>\n                    ), integrating structure\u2010based ADMETlab3.0 estimation, offers a practical complement to conventional PBPK modeling for early drug development.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70314","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:24:48Z","timestamp":1785558288000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Machine Learning Enables Rapid Prediction of Acid\u2010Reducing Agent Drug Interactions: A Streamlined Complement to\n                    <scp>PBPK<\/scp>\n                    Modeling"],"prefix":"10.1002","volume":"15","author":[{"given":"Yuanfang","family":"Qin","sequence":"first","affiliation":[{"name":"Department of Pharmacy The Third Xiangya Hospital, Central South University  Changsha China"},{"name":"Center for Clinical Pharmacology The Third Xiangya Hospital, Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lehua","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Clinical Pharmacology The Third Xiangya Hospital, Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai PharmoGo Co., Ltd  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghui","family":"Zuo","sequence":"additional","affiliation":[{"name":"Changsha Xutong Technology Co., Ltd  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8852-6490","authenticated-orcid":false,"given":"Hongyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Research Center Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, State Key Laboratory of Complex Severe and Rare Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5930-586X","authenticated-orcid":false,"given":"Guoping","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Clinical Pharmacology The Third Xiangya Hospital, Central South University  Changsha China"},{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6711-4251","authenticated-orcid":false,"given":"Qi","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The Third Xiangya Hospital, Central South University  Changsha China"},{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2165\/11593990-000000000-00000"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-014-0144-0"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp400256h"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2012.73"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp400403s"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1293.2007.00456.x"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.1166"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2016.04.004"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-022-03274-2"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2013.09.008"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2010.06.003"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14541"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3732"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.4c00946"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.0c05846"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.8b00785"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.118.082966"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-019-0384-1"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dmpk.2026.101523"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2026.112049"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-021-00659-w"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-018-0635-8"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200645050-00006"},{"key":"e_1_2_10_25_1","unstructured":"U.S. Food and Drug Administration https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2012\/202324Orig1s000ClinPharmR.pdf."},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-017-3308-7"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1018918316253"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270005276738"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2025.140059"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-020-00463-y"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0000000000000212"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.337"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2009.03466.x"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.2146\/ajhp070226"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.45"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270009346061"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00637632"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.588"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270009333854"},{"key":"e_1_2_10_40_1","volume-title":"Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs\u2014General Considerations","author":"FDA","year":"2014"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14081530"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2123"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-025-01034-9"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2024.107424"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci025626i"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-020-00511-7"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.3c00016"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270007304777"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkg089"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.678"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp4005595"},{"key":"e_1_2_10_52_1","unstructured":"U.S. Food and Drug Administration https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2017\/209091Orig1s000MedR.pdf."},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-016-3020-z"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-42165-3"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2018.10.032"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3289"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics17111413"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c00340"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.9b04162"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70314","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.70314","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70314","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:11:10Z","timestamp":1787199070000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70314"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":58,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/psp4.70314"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70314","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]},"assertion":[{"value":"2026-02-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70314"}}