{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T22:17:13Z","timestamp":1792534633346,"version":"4.5.0"},"reference-count":55,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Psychopharmacol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>The efficacy of clozapine in treatment-resistant schizophrenia is limited by significant pharmacokinetic variability due to genetic polymorphisms, drug interactions, and environmental factors, necessitating personalized dosing strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>This study aimed at developing a physiologically based pharmacokinetic\/pharmacodynamic (PBPK\/PD) model integrating genetics and clinical factors to guide precision dosing of clozapine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      A simulation study was conducted to develop a PBPK\/PD model using R (\n                      <jats:italic toggle=\"yes\">mrgsolve<\/jats:italic>\n                      ) to simulate clozapine plasma and brain concentrations, multireceptor occupancies, clinical efficacy, and safety risks (agranulocytosis, seizures, cardiotoxicity). The model incorporated multiple genetic profiles (\n                      <jats:italic toggle=\"yes\">CYP1A2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">CYP2D6<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">ABCB1<\/jats:italic>\n                      ), drug interactions (with fluvoxamine and carbamazepine), smoking effects, and ethnic-specific adjustments. Simulations evaluated steady-state outcomes, therapeutic drug monitoring (TDM) protocols, and optimal dosing. Validation used literature datasets, with sensitivity analyses assessing enzyme activity impacts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The model demonstrated high predictive accuracy, with simulations revealing substantial variability in clozapine concentrations, primarily driven by\n                      <jats:italic toggle=\"yes\">CYP1A2<\/jats:italic>\n                      polymorphisms. Model-informed genotype-guided dosing achieved therapeutic levels, markedly improving clinical response and significantly reducing adverse events. Fluvoxamine posed high-risk interactions, particularly in poor metabolizers, while smoking reduced concentrations, requiring dose adjustments. Ethnic-specific dosing addressed population variability, with tailored recommendations for special populations (elderly, pediatric). Sensitivity analyses identified glutathione status as a key determinant in agranulocytosis risk, underscoring the importance of genetic polymorphisms in glutathione S-transferases (\n                      <jats:italic toggle=\"yes\">GSTT1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">GSTM1<\/jats:italic>\n                      ) in safety outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>This PBPK\/PD model provides a robust framework for precision clozapine therapy, supporting genotype-guided dosing and TDM to optimize efficacy and safety. The implementation of pharmacogenetic testing could transform clinical practice, offering a framework for optimized resource utilization and risk minimization.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/02698811261424205","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T13:59:03Z","timestamp":1773237543000},"page":"574-585","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Precision dosing of clozapine: A physiologically based pharmacokinetic\/pharmacodynamic model integrating genetic polymorphisms and clinical outcomes"],"prefix":"10.1177","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8837-299X","authenticated-orcid":false,"given":"Archana","family":"Mishra","sequence":"first","affiliation":[{"name":"Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4063-9178","authenticated-orcid":false,"given":"Rituparna","family":"Maiti","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7339-1773","authenticated-orcid":false,"given":"Debasish","family":"Hota","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4002009"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1994.tb04385.x"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2903"},{"key":"e_1_3_3_5_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200039020-00004"},{"key":"e_1_3_3_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004714-199808000-00011"},{"key":"e_1_3_3_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01470-z"},{"key":"e_1_3_3_8_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.09.51"},{"key":"e_1_3_3_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e3181f0a1a2"},{"key":"e_1_3_3_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2003.09.010"},{"key":"e_1_3_3_11_1","unstructured":"Dragovic S (2013) Role of Genetic Polymorphisms of Drug Metabolising Enzymes in Idiosyncratic Drug Reactions In Vitro to In Vivo Translation Research and graduation internal. 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