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Using a high virtualization MIPD\u2010VT approach (Simcyp version 21), we predicted the steady\u2010state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600\u2009ng\/mL in hospitalized patients with treatment\u2010resistant schizophrenia (<jats:italic>N<\/jats:italic>\u2009=\u200911). We confirmed that high virtualization MIPD\u2010VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady\u2010state clozapine concentrations were overpredicted two to four\u2010fold. This work supports the application of a high virtualization MIPD\u2010VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug\u2013drug interactions, particularly with fluvoxamine augmentation.<\/jats:p>","DOI":"10.1002\/psp4.13093","type":"journal-article","created":{"date-parts":[[2024,1,20]],"date-time":"2024-01-20T06:43:46Z","timestamp":1705733026000},"page":"424-436","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Virtual twins for model\u2010informed precision dosing of clozapine in patients with treatment\u2010resistant schizophrenia"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2317-3233","authenticated-orcid":false,"given":"Sam","family":"Mostafa","sequence":"first","affiliation":[{"name":"Centre for Medicine Use and Safety Monash University  Parkville Victoria Australia"},{"name":"MyDNA Life Australia Limited  Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4163-8241","authenticated-orcid":false,"given":"Reza","family":"Rafizadeh","sequence":"additional","affiliation":[{"name":"BC Mental Health and Substance Use Services, BC Psychosis Program Lower Mainland Pharmacy Services  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1008-5223","authenticated-orcid":false,"given":"Thomas M.","family":"Polasek","sequence":"additional","affiliation":[{"name":"Centre for Medicine Use and Safety Monash University  Parkville Victoria Australia"},{"name":"Certara  Princeton New Jersey USA"},{"name":"Department of Clinical Pharmacology Royal Adelaide Hospital  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6303-8696","authenticated-orcid":false,"given":"Chad A.","family":"Bousman","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Melbourne Neuropsychiatry Centre University of Melbourne and Melbourne Health  Melbourne Victoria Australia"},{"name":"Alberta Children's Hospital Research Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Departments of Medical Genetics, Psychiatry, Physiology and Pharmacology, and Community Health Sciences University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-844X","authenticated-orcid":false,"given":"Amin","family":"Rostami\u2010Hodjegan","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research (CAPKR), School of Health Sciences University of Manchester  Manchester UK"},{"name":"Simcyp Division Certara UK Limited  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2067-198X","authenticated-orcid":false,"given":"Robert","family":"Stowe","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of British Columbia  Vancouver British Columbia Canada"},{"name":"Djavid Mowafaghian Centre for Brain Health University of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Neurology (Medicine) University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4965-9175","authenticated-orcid":false,"given":"Prescilla","family":"Carrion","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie J.","family":"Sheffield","sequence":"additional","affiliation":[{"name":"MyDNA Life Australia Limited  Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5715-1534","authenticated-orcid":false,"given":"Carl M. 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