{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:50:41Z","timestamp":1791273041202,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"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":["Clin Pharma and Therapeutics"],"abstract":"\n Cannabidiol (CBD) inhibits multiple cytochrome P450 (CYP450) enzymes\n in vitro<\/jats:italic>\n via reversible and time\u2010dependent mechanisms, raising concerns for metabolic drug\u2013drug interactions (DDIs). Clinical DDI data for CBD are limited, and the translation of\n in vitro<\/jats:italic>\n derived inhibition parameters into\n in vivo<\/jats:italic>\n DDI predictions remains uncertain. We implemented a stepwise, model\u2010informed framework to evaluate CBD\u2010mediated metabolic DDIs using (i) basic, (ii) mechanistic static (MSM), and (iii) physiologically based pharmacokinetic (PBPK) models. The basic model and MSM incorporated\n in vitro<\/jats:italic>\n inhibition parameters for CBD and its primary active metabolite, 7\u2010hydroxycannabidiol (7\u2010OH\u2010CBD), to identify sensitive metabolic pathways. A PBPK model for CBD and 7\u2010OH\u2010CBD was developed and validated against clinical pharmacokinetic data, then used to simulate DDIs. Where necessary, inhibition parameters were refined using the PBPK model to capture clinical observations, and the optimized parameters were used to revisit the basic model and MSM, facilitating comparison across modeling approaches. The MSM predicted 3.6\u2010, 4.1\u2010, and 2.2\u2010fold increases in exposure of sensitive CYP1A2, CYP2C9, and CYP3A4 substrates, respectively, and a strong CYP2C19\u2010mediated interaction. In contrast, the PBPK model predicted lower DDI magnitudes consistent with clinical data, identifying CYP2C19 inhibition as the most clinically relevant liability, with a moderate interaction risk for sensitive substrates, while CYP1A2 inhibition increased sensitive substrate exposure twofold. The validated PBPK model was applied to evaluate exposure in special populations and DDI risk with commonly co\u2010prescribed medications. Overall, this framework reconciles\n in vitro<\/jats:italic>\n and clinical DDI data and supports population\u2010specific assessment of CBD\u2010mediated DDIs across diverse clinical scenarios.\n <\/jats:p>","DOI":"10.1002\/cpt.70509","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:53:26Z","timestamp":1791269606000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating Static and Dynamic Models to Predict Cannabidiol\u2010Mediated Metabolic Drug\u2013Drug Interactions"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8479-3471","authenticated-orcid":false,"given":"Sulafa","family":"Al Sahlawi","sequence":"first","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics College of Pharmacy, University of Florida Orlando Florida USA"},{"name":"Department of Pharmaceutical Sciences College of Clinical Pharmacy, King Faisal University Al\u2010Ahsa Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9537-6769","authenticated-orcid":false,"given":"Bassma","family":"Eltanameli","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics College of Pharmacy, University of Florida Orlando Florida USA"},{"name":"Department of Pharmaceutics, Faculty of Pharmacy Mansoura University Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7932-8599","authenticated-orcid":false,"given":"Brian","family":"Cicali","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics College of Pharmacy, University of Florida Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2619-0343","authenticated-orcid":false,"given":"Rodrigo","family":"Cristofoletti","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics College of Pharmacy, University of Florida Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"e_1_2_11_1_1","first-page":"1","article-title":"Phytochemistry of Cannabis sativa L","volume":"103","author":"ElSohly M.A.","year":"2017","journal-title":"Prog. 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AOAC Int."},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1124\/dmd.121.000734","article-title":"Comprehensive predictions of cytochrome P450 (P450)\u2010mediated in\u00a0vivo cannabinoid\u2010drug interactions based on reversible and time\u2010dependent P450 inhibition in human liver Microsomes","volume":"50","author":"Bansal S.","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1124\/dmd.121.000442","article-title":"Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis\u2010drug interactions","volume":"49","author":"Nasrin S.","year":"2021","journal-title":"Drug Metab. Dispos."},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","DOI":"10.3390\/pharmaceutics16040484","article-title":"CBD and THC in special populations: pharmacokinetics and drug\u2013drug interactions","volume":"16","author":"Qian L.","year":"2024","journal-title":"Pharmaceutics."},{"key":"e_1_2_11_8_1","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).M12 Drug Interaction Studies(2024) ."},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","DOI":"10.1111\/cts.70119","article-title":"Physiologically based pharmacokinetic modeling of Cannabidiol, Delta\u20109\u2010tetrahydrocannabinol, and their metabolites in healthy adults after administration by multiple routes","volume":"18","author":"Qian L.","year":"2025","journal-title":"Clin. Transl. Sci."},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","DOI":"10.1111\/cts.70401","article-title":"Using a PBPK model incorporating lymphatic absorption to predict food effect, multiple dosing, and hepatic impairment of Cannabidiol","volume":"18","author":"Qian L.","year":"2025","journal-title":"Clin. Transl. Sci."},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/psp4.12908","article-title":"Verifying in\u00a0vitro\u2010determined enzyme contributions to cannabidiol clearance for exposure predictions in human through physiologically\u2010based pharmacokinetic modeling","volume":"12","author":"Yeung C.H.T.","year":"2023","journal-title":"CPT Pharmacometrics Syst. Pharmacol."},{"key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1124\/dmd.122.001128","article-title":"A physiologically\u2010based pharmacokinetic model for Cannabidiol in healthy adults, Hepatically\u2010impaired adults, and children","volume":"51","author":"Bansal S.","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1124\/dmd.121.000823","article-title":"Prediction of carboxylesterase 1\u2010mediated in\u00a0vivo drug interaction between methylphenidate and cannabinoids using static and physiologically based pharmacokinetic models","volume":"50","author":"Qian Y.","year":"2022","journal-title":"Drug Metab. 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Pharma Therap."},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/cpdd.665","article-title":"A phase 1, open\u2010label, pharmacokinetic trial to investigate possible drug\u2010drug interactions between Clobazam, Stiripentol, or valproate and Cannabidiol in healthy subjects","volume":"8","author":"Morrison G.","year":"2019","journal-title":"Clin Pharmacol Drug Dev."},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1124\/dmd.120.000073","article-title":"Predicting the potential for cannabinoids to precipitate pharmacokinetic drug interactions via reversible inhibition or inactivation of major cytochromes P450","volume":"48","author":"Bansal S.","year":"2020","journal-title":"Drug Metab. 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Mass Spectrom."},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1007\/s11095-024-03703-4","article-title":"Relative performance of volume of distribution prediction methods for lipophilic drugs with uncertainty in LogP value","volume":"41","author":"Coutinho A.L.","year":"2024","journal-title":"Pharm. Res."},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s40263-018-0578-5","article-title":"A phase I, randomized, double\u2010blind, placebo\u2010controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified Cannabidiol in healthy subjects","volume":"32","author":"Taylor L.","year":"2018","journal-title":"CNS Drugs"},{"key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/epi.16419","article-title":"A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects","volume":"61","author":"Crockett J.","year":"2020","journal-title":"Epilepsia"},{"key":"e_1_2_11_23_1","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s40262-019-00841-6","article-title":"A phase I, open\u2010label, parallel\u2010group, single\u2010dose trial of the pharmacokinetics, safety, and tolerability of Cannabidiol in subjects with mild to severe renal impairment","volume":"59","author":"Tayo B.","year":"2020","journal-title":"Clin. 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Pharmacol."},{"key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/cpt.3537","article-title":"Impact of CYP2C19 phenotype on Escitalopram response in geriatrics: based on physiologically\u2010based pharmacokinetic modeling and clinical observation","volume":"117","author":"Jang Y.J.","year":"2025","journal-title":"Clinical Pharmacology & Therapeutics."},{"key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/psp4.12794","article-title":"Prediction of CYP\u2010mediated DDIs involving inhibition: approaches to address the requirements for system qualification of the Simcyp simulator","volume":"11","author":"Kilford P.J.","year":"2022","journal-title":"CPT Pharmacometrics Syst. 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Pharmacokinet."},{"key":"e_1_2_11_44_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1097\/JCP.0000000000001427","article-title":"Citalopram and Cannabidiol: in\u00a0vitro and in\u00a0vivo evidence of pharmacokinetic interactions relevant to the treatment of anxiety disorders in young people","volume":"41","author":"Anderson L.L.","year":"2021","journal-title":"J. Clin. Psychopharmacol."},{"key":"e_1_2_11_45_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.dmd.2025.100096","article-title":"Predicting in\u00a0vivo cannabinoid\u2010drug interactions mediated via inhibition of UDP\u2010glucuronosyltransferases using in\u00a0vitro studies and physiologically based pharmacokinetic modeling and simulations","volume":"53","author":"Bansal S.","year":"2025","journal-title":"Drug Metab. Dispos."},{"key":"e_1_2_11_46_1","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/cpt.3504","article-title":"A phase I trial of the pharmacokinetic interaction between Cannabidiol and tacrolimus","volume":"117","author":"So G.C.","year":"2025","journal-title":"Clin. Pharma Therap."},{"key":"e_1_2_11_47_1","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1002\/cpdd.1262","article-title":"Pharmacokinetic drug\u2010drug interaction with Coadministration of Cannabidiol and Everolimus in a phase 1 healthy volunteer trial","volume":"12","author":"Wray L.","year":"2023","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"e_1_2_11_48_1","doi-asserted-by":"crossref","DOI":"10.1111\/cts.70152","article-title":"Inhibition of tacrolimus metabolism by Cannabidiol and its metabolites in\u00a0vitro","volume":"18","author":"So G.C.","year":"2025","journal-title":"Clin. Transl. 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