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1. Do asian patients require only half of the clozapine dose prescribed for caucasians? A critical overview

Author

Jose de Leon, Anto P Rajkumar, Arun R Kaithi, Georgios Schoretsanitis, John M Kane, Chuan-Yue Wang, Yi-Lang Tang, Shih-Ku Lin, Kyung Sue Hong, Saeed Farooq, Chee H Ng, Can-Jun Ruan, and Chittaranjan Andrade

Subjects
asian continental ancestry group/genetics, blood, cyp1a2, clozapine, drug labeling, india, pharmacokinetics, sex, smoking, Psychiatry, RC435-571
Abstract

Since 1997, studies have found that Asians need lower clozapine doses than Caucasians. Caucasians with average clozapine metabolism may need from 300 to 600 mg/day to reach the therapeutic range (350 ng/ml). Thus, serum clozapine concentration-to-dose (C/D) ratios typically range between 0.60 (male smokers) and 1.20 (female non-smokers). A 2019 systematic review of clozapine levels demonstrated weighted mean C/D ratios of 1.57 in 876 East Asians and 1.07 in 1147 Caucasians (P < .001). In Asian countries, average clozapine doses are lower than 300 mg/day. After sex and smoking stratification in 5 Asian samples with clozapine concentrations, the clozapine dose required to reach 350 ng/ml in female non-smokers ranged from 145 to 189 mg/day and in male smokers, from 259 to 294 mg/day. Thus, in Asian patients with average metabolism (with no inducers other than smoking, with no inhibitors, and in the absence of extreme obesity), the dose needed for clinical response may range between 150 mg/day for female non-smokers to 300 mg/day for male smokers. Clozapine levels may help personalize dosing in clozapine poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Asian PMs may need very low doses (50-150 mg/day) to obtain therapeutic concentrations. About 10% (range 2-13%) of Asians are genetic PM cases. Other PMs are patients taking CYP1A2 inhibitors such as fluvoxamine, oral contraceptives, and valproate. Temporary clozapine PM status may occur during severe systemic infections/inflammations with fever and C-reactive protein (CRP) elevations. Asian UMs include patients taking potent inducers such as phenytoin, and rarely, valproate.

Published
2020
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2. Correction: An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

Author

Jose de Leon, Georgios Schoretsanitis, Robert L. Smith, Espen Molden, Anssi Solismaa, Niko Seppälä, Miloslav Kopeček, Patrik Švancer, Ismael Olmos, Carina Ricciardi, Celso Iglesias-Garcia, Ana Iglesias-Alonso, Edoardo Spina, Can-Jun Ruan, Chuan-Yue Wang, Gang Wang, Yi-Lang Tang, Shih-Ku Lin, Hsien-Yuan Lane, Yong Sik Kim, Se Hyun Kim, Anto P. Rajkumar, Dinora F. González-Esquivel, Helgi Jung-Cook, Trino Baptista, Christopher Rohde, Jimmi Nielsen, Hélène Verdoux, Clelia Quiles, Emilio J. Sanz, Carlos De Las Cuevas, Dan Cohen, Peter F.J. Schulte, Aygün Ertuğrul, A. Elif Anıl Yağcıoğlu, Nitin Chopra, Betsy McCollum, Charles Shelton, Robert O. Cotes, Arun R. Kaithi, John M. Kane, Saeed Farooq, Chee H. Ng, John Bilbily, Christoph Hiemke, Carlos López-Jaramillo, Ian McGrane, Fernando Lana, Chin B. Eap, Manuel Arrojo-Romero, Flavian Ş. Rădulescu, Erich Seifritz, Susanna Every-Palmer, Chad A. Bousman, Emmanuel Bebawi, Rahul Bhattacharya, Deanna L. Kelly, Yuji Otsuka, Judit Lazary, Rafael Torres, Agustin Yecora, Mariano Motuca, Sherry K.W. Chan, Monica Zolezzi, Sami Ouanes, Domenico De Berardis, Sandeep Grover, Ric M. Procyshyn, Richard A. Adebayo, Oleg O. Kirilochev, Andrey Soloviev, Konstantinos N. Fountoulakis, Alina Wilkowska, Wiesław J. Cubała, Muhammad Ayub, Alzira Silva, Raphael M. Bonelli, José M. Villagrán-Moreno, Benedicto Crespo-Facorro, Henk Temmingh, Eric Decloedt, Maria R. Pedro, Hiroyoshi Takeuchi, Masaru Tsukahara, Gerhard Gründer, Marina Sagud, Andreja Celofiga, Dragana Ignjatovic Ristic, Bruno B. Ortiz, Helio Elkis, António J. Pacheco Palha, Adrián LLerena, Emilio Fernandez-Egea, Dan Siskind, Abraham Weizman, Rim Masmoudi, Shamin Mohd Saffian, Jonathan G. Leung, Peter F. Buckley, Stephen R. Marder, Leslie Citrome, Oliver Freudenreich, Christoph U. Correll, Daniel J. Müller, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Psychiatry and Mental health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Pharmacology (medical), General Medicine
Published
2022
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3. An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

Author

Jose de Leon, Georgios Schoretsanitis, Robert L. Smith, Espen Molden, Anssi Solismaa, Niko Seppälä, Miloslav Kopeček, Patrik Švancer, Ismael Olmos, Carina Ricciardi, Celso Iglesias-Garcia, Ana Iglesias-Alonso, Edoardo Spina, Can-Jun Ruan, Chuan-Yue Wang, Gang Wang, Yi-Lang Tang, Shih-Ku Lin, Hsien-Yuan Lane, Yong Sik Kim, Se Hyun Kim, Anto P. Rajkumar, Dinora F. González-Esquivel, Helgi Jung-Cook, Trino Baptista, Christopher Rohde, Jimmi Nielsen, Hélène Verdoux, Clelia Quiles, Emilio J. Sanz, Carlos De Las Cuevas, Dan Cohen, Peter F.J. Schulte, Aygün Ertuğrul, A. Elif Anıl Yağcıoğlu, Nitin Chopra, Betsy McCollum, Charles Shelton, Robert O. Cotes, Arun R. Kaithi, John M. Kane, Saeed Farooq, Chee H. Ng, John Bilbily, Christoph Hiemke, Carlos López-Jaramillo, Ian McGrane, Fernando Lana, Chin B. Eap, Manuel Arrojo-Romero, Flavian Ş. Rădulescu, Erich Seifritz, Susanna Every-Palmer, Chad A. Bousman, Emmanuel Bebawi, Rahul Bhattacharya, Deanna L. Kelly, Yuji Otsuka, Judit Lazary, Rafael Torres, Agustin Yecora, Mariano Motuca, Sherry K.W. Chan, Monica Zolezzi, Sami Ouanes, Domenico De Berardis, Sandeep Grover, Ric M. Procyshyn, Richard A. Adebayo, Oleg O. Kirilochev, Andrey Soloviev, Konstantinos N. Fountoulakis, Alina Wilkowska, Wiesław J. Cubała, Muhammad Ayub, Alzira Silva, Raphael M. Bonelli, José M. Villagrán-Moreno, Benedicto Crespo-Facorro, Henk Temmingh, Eric Decloedt, Maria R. Pedro, Hiroyoshi Takeuchi, Masaru Tsukahara, Gerhard Gründer, Marina Sagud, Andreja Celofiga, Dragana Ignjatovic Ristic, Bruno B. Ortiz, Helio Elkis, António J. Pacheco Palha, Adrián LLerena, Emilio Fernandez-Egea, Dan Siskind, Abraham Weizman, Rim Masmoudi, Shamin Mohd Saffian, Jonathan G. Leung, Peter F. Buckley, Stephen R. Marder, Leslie Citrome, Oliver Freudenreich, Christoph U. Correll, and Daniel J. Müller

Subjects
Adult, Male, CYP1A2, mortality/drug effects, clozapine/therapeutic use, American continental ancestry group, Asian continental ancestry group, clozapine/adverse effects, clozapine/blood, clozapine/metabolism, clozapine/toxicity, drug labeling, European continental ancestry group, infection, inflammation, Native, sex, smoking, Asian People, Humans, Pharmacology (medical), Clozapine, Valproic Acid, Native - American continental ancestry group - Asian continental ancestry group - clozapine/adverse effects - clozapine/blood - clozapine/metabolism - clozapine/therapeutic use - clozapine/toxicity - CYP1A2 - drug labeling - European continental ancestry group - infection - inflammation - mortality/drug effects - sex - smoking, General Medicine, Psychiatry and Mental health, C-Reactive Protein, Female, Antipsychotic Agents
Abstract

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Published
2021
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