An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

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 Ertuǧrul; A. Elif Anll Yaǧcloǧlu; 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 Rǎdulescu; 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

doi:10.1055/a-1625-6388

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

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 KimSe 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 Ertuǧrul, A. Elif Anll Yaǧcloǧlu, 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 Rǎdulescu, 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

精神・神経科学

研究成果: Review article › 査読

48 被引用数 (Scopus)

抄録

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.

本文言語	English
ページ（範囲）	73-86
ページ数	14
ジャーナル	Pharmacopsychiatry
巻	55
号	2
DOI	https://doi.org/10.1055/a-1625-6388
出版ステータス	Published - 2022 3月 1

ASJC Scopus subject areas

精神医学および精神衛生
薬理学（医学）

UN SDG

この成果は、次の持続可能な開発目標に貢献しています

文献へのアクセス

10.1055/a-1625-6388

他のファイルとリンク

フィンガープリント

「An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル

De Leon, J., Schoretsanitis, G., Smith, R. L., Molden, E., Solismaa, A., Seppälä, N., Kopeček, M., Švancer, P., Olmos, I., Ricciardi, C., Iglesias-Garcia, C., Iglesias-Alonso, A., Spina, E., Ruan, C. J., Wang, C. Y., Wang, G., Tang, Y. L., Lin, S. K., Lane, H. Y., ... Müller, D. J. (2022). An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels. Pharmacopsychiatry, 55(2), 73-86. https://doi.org/10.1055/a-1625-6388

De Leon, J, Schoretsanitis, G, Smith, RL, Molden, E, Solismaa, A, Seppälä, N, Kopeček, M, Švancer, P, Olmos, I, Ricciardi, C, Iglesias-Garcia, C, Iglesias-Alonso, A, Spina, E, Ruan, CJ, Wang, CY, Wang, G, Tang, YL, Lin, SK, Lane, HY, Kim, YS, Kim, SH, Rajkumar, AP, González-Esquivel, DF, Jung-Cook, H, Baptista, T, Rohde, C, Nielsen, J, Verdoux, H, Quiles, C, Sanz, EJ, De Las Cuevas, C, Cohen, D, Schulte, PFJ, Ertuǧrul, A, Anll Yaǧcloǧlu, AE, Chopra, N, McCollum, B, Shelton, C, Cotes, RO, Kaithi, AR, Kane, JM, Farooq, S, Ng, CH, Bilbily, J, Hiemke, C, López-Jaramillo, C, McGrane, I, Lana, F, Eap, CB, Arrojo-Romero, M, Rǎdulescu, F, Seifritz, E, Every-Palmer, S, Bousman, CA, Bebawi, E, Bhattacharya, R, Kelly, DL, Otsuka, Y, Lazary, J, Torres, R, Yecora, A, Motuca, M, Chan, SKW, Zolezzi, M, Ouanes, S, De Berardis, D, Grover, S, Procyshyn, RM, Adebayo, RA, Kirilochev, OO, Soloviev, A, Fountoulakis, KN, Wilkowska, A, Cubała, WJ, Ayub, M, Silva, A, Bonelli, RM, Villagrán-Moreno, JM, Crespo-Facorro, B, Temmingh, H, Decloedt, E, Pedro, MR, Takeuchi, H, Tsukahara, M, Gründer, G, Sagud, M, Celofiga, A, Ignjatovic Ristic, D, Ortiz, BB, Elkis, H, Pacheco Palha, AJ, Llerena, A, Fernandez-Egea, E, Siskind, D, Weizman, A, Masmoudi, R, Mohd Saffian, S, Leung, JG, Buckley, PF, Marder, SR, Citrome, L, Freudenreich, O, Correll, CU & Müller, DJ 2022, 'An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels', Pharmacopsychiatry, vol. 55, no. 2, pp. 73-86. https://doi.org/10.1055/a-1625-6388

@article{1d9bce0146b3494a8cf32ad3486ab905,

title = "An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels",

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.",

keywords = "American continental ancestry group, Asian continental ancestry group, CYP1A2, European continental ancestry group, Native, clozapine/adverse effects, clozapine/blood, clozapine/metabolism, clozapine/therapeutic use, clozapine/toxicity, drug labeling, infection, inflammation, mortality/drug effects, sex, smoking.",

author = "{De Leon}, Jose and Georgios Schoretsanitis and Smith, {Robert L.} and Espen Molden and Anssi Solismaa and Niko Sepp{\"a}l{\"a} and Miloslav Kope{\v c}ek and Patrik {\v S}vancer and Ismael Olmos and Carina Ricciardi and Celso Iglesias-Garcia and Ana Iglesias-Alonso and Edoardo Spina and Ruan, {Can Jun} and Wang, {Chuan Yue} and Gang Wang and Tang, {Yi Lang} and Lin, {Shih Ku} and Lane, {Hsien Yuan} and Kim, {Yong Sik} and Kim, {Se Hyun} and Rajkumar, {Anto P.} and Gonz{\'a}lez-Esquivel, {Dinora F.} and Helgi Jung-Cook and Trino Baptista and Christopher Rohde and Jimmi Nielsen and H{\'e}l{\`e}ne Verdoux and Clelia Quiles and Sanz, {Emilio J.} and {De Las Cuevas}, Carlos and Dan Cohen and Schulte, {Peter F.J.} and Ayg{\"u}n Ertuǧrul and {Anll Yaǧcloǧlu}, {A. Elif} and Nitin Chopra and Betsy McCollum and Charles Shelton and Cotes, {Robert O.} and Kaithi, {Arun R.} and Kane, {John M.} and Saeed Farooq and Ng, {Chee H.} and John Bilbily and Christoph Hiemke and Carlos L{\'o}pez-Jaramillo and Ian McGrane and Fernando Lana and Eap, {Chin B.} and Manuel Arrojo-Romero and Flavian Rǎdulescu and Erich Seifritz and Susanna Every-Palmer and Bousman, {Chad A.} and Emmanuel Bebawi and Rahul Bhattacharya and Kelly, {Deanna L.} and Yuji Otsuka and Judit Lazary and Rafael Torres and Agustin Yecora and Mariano Motuca and Chan, {Sherry K.W.} and Monica Zolezzi and Sami Ouanes and {De Berardis}, Domenico and Sandeep Grover and Procyshyn, {Ric M.} and Adebayo, {Richard A.} and Kirilochev, {Oleg O.} and Andrey Soloviev and Fountoulakis, {Konstantinos N.} and Alina Wilkowska and Cuba{\l}a, {Wies{\l}aw J.} and Muhammad Ayub and Alzira Silva and Bonelli, {Raphael M.} and Villagr{\'a}n-Moreno, {Jos{\'e} M.} and Benedicto Crespo-Facorro and Henk Temmingh and Eric Decloedt and Pedro, {Maria R.} and Hiroyoshi Takeuchi and Masaru Tsukahara and Gerhard Gr{\"u}nder and Marina Sagud and Andreja Celofiga and {Ignjatovic Ristic}, Dragana and Ortiz, {Bruno B.} and Helio Elkis and {Pacheco Palha}, {Ant{\'o}nio J.} and Adri{\'a}n Llerena and Emilio Fernandez-Egea and Dan Siskind and Abraham Weizman and Rim Masmoudi and {Mohd Saffian}, Shamin and Leung, {Jonathan G.} and Buckley, {Peter F.} and Marder, {Stephen R.} and Leslie Citrome and Oliver Freudenreich and Correll, {Christoph U.} and M{\"u}ller, {Daniel J.}",

note = "Funding Information: reports consultation fees from Roche, Sunovion, Merck, Boehringer Ingelheim and Otsuka. He reports research support from Boehringer-Ingelheim, and GW Pharma. Dr. Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: AbbVie, Acadia, Alexza, Alkermes, Allergan, Angelini, Astellas, AstraZeneca, Avanir, Axsome, BioXcel, Boehringer Ingel-heim, Bristol-Myers Squibb, Cadent Therapeutics, Eisai, Eli Lilly, Forum, Genentech, Impel, Indivior, Intra-Cellular Therapies, Jans-sen, Jazz, Karuna, Lundbeck, Luye, Lyndra, Medavante-Prophase, Meiji, Merck, Medivation, Mylan, Neurocrine, NeuroRx, Novartis, Noven, Osmotica, Otsuka, Pfizer, Reckitt ?enckiser, Relmada, Re-viva, Sage, Shire, Sunovion, Takeda, Teva, University of Arizona, Valeant, Vanda, and one-o ? ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research. Dr. Freudenreich has the following financial relationship with a commercial interest to disclose (recipient SELF; content area SCHIZOPHRENIA): Alkermes – Research grant (to institution), consultant honoraria (Advisory Board); Avanir – Research grant (to institution); Janssen – Research grant (to institution), consultant honoraria (Advisory Board); Integral - Consultant honoraria; Neurocrine – Consultant honoraria (Advisory Board); Novartis – Consultant honoraria; Otsuka – Research grant (to institution); Roche – Consultant honoraria; Springer Verlag – Royalties (medical writer); Elsevier – Honoraria (medical editing); Global Medical Education – Honoraria (CME speaker and content developer); Medscape – Honoraria (CME speaker); American Psychiatric Association – Consultant honoraria (SMI Adviser); Wolters-Kluwer – Royalties (content developer); UpToDate – Royalties, honoraria (content developer and editor, including for a chapter on clozapine). Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Damitsa, Gedeon Richter, Hikma, IntraCellular Therapies, Janssen/ J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedIn-Cell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of LB Pharma. Dr. M{\"u}ller reports he has been a co-investigator for two pharmacogenetic studies where genetic test kits were provided as an in-kind contribution by Myriad Neuroscience. He did not receive any payments or any equity, stocks, or options from any pharmacogenetic companies. He is also a co-inventor of two patents assessing risk for antipsychotic-induced weight gain (pending). Funding Information: Olmos, Ricciardi, Iglesias-Garcia, Iglesias-Alonso, Spina, Ruan, Chuan-Yue Wang, Gang Wang, Tang, Lin, Lane, Rajkumar, Gonz{\'a}lez-Esquivel, Jung-Cook, Baptista, Rohde, Nielsen, Verdoux, Quiles, Sanz, De las Cuevas, Cohen, Schulte, Chopra, McCollum, Shelton, Kaithi, Farooq, McGrane, Lana, Arrojo-Romero, R{\u a}dulescu, Every-Palmer, Bebawi, Bhattacharya, Otsuka, Lazary, Torres, Yecora, Motuca, Chan, Zolezzi, Ouanes, De Berardis, Grover, Kirilochev, Soloviev, Ayub, Silva, Bonelli, Temmingh, Decloedt, Pedro, Pacheco Palha, LLerena, Fernandez-Egea, Siskind, Masmoudi, Mohd Sa Can, Leung and ?uckley. In the last 3 years several authors report conflicts of interests. Dr. Sepp{\"a}l{\"a} is permanent medical advisor, received lecture fees and is an advisory board member from Viatris that markets clozapine in Finland and other European countries. Dr. Kope{\v c}ek participated in speakers/advisory boards and lectured with the support of Angelini, Janssen Pharmaceuticals, Lundbeck and Richter Gedeon. Dr. Yong Sik Kim received grants, research support and honoraria from Janssen, Otsuka, Whan in Pharm and Bukwang Pharm (Sumitomo Dannipon Pharma). Dr. Se Hyun Kim received research grants from and/or served as a lecturer for Janssen, Eli Lilly, and Dongwha. Dr. Ertuğrul has received speaker{\textquoteright}s honoraria from Abdi İbrahim Otsuka. Dr. Anıl Yağcıoğlu has received speaker{\textquoteright}s honoraria and consulting fees from Janssen and Abdi İbrahim Otsuka. Dr. Cotes has received research funding from Otsuka, Lundbeck, Roche, Alkermes, and is a consultant for Saladax Biomedical. Dr. Kane reports personal fees from Alkermes, personal fees from Allergan, personal fees from Bristol-Myers Squibb, personal fees from IntraCellular Therapies, Janssen, Lundbeck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Sunovion, Takeda, Teva, outside-the-submitted work from LB Pharma, MedAvante and The Vanguard Research Group. Dr. Ng had served as consultant for Grunbiotics, Lundbeck, Servier, and Janssen-Cilag, and received research speaker honoraria from Servier, Janssen-Cilag and Pfizer.IMcG received royalties from Hogrefe Publishing Corp. T.L. Dr. Bilbily is supported by the National Institute on Drug Abuse training grant 5T32DA007261-30 (MPI). Dr. Hiemke received speaker{\textquoteright}s honoraria from Otsuka. Dr. L{\'o}pez-Jaramillo reports financial support for research from Financial support from the National Institute of Mental Health, USA, MinCiencias, Colombia and the Universidad de An-tioquia, Colombia. Dr. Eap received honoraria for conferences or teaching CME courses from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Vifor-Pharma, and Zeller. Dr. Seifritz has received honoraria from Schwabe GmbH for educational lectures. He has further received educational grants and consulting fees from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Recordati, Vifor, Sunovion, and Mepha. Dr. Bousman is a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Phar-macogene Variation Consortium (PharmVar). Dr. Kelly has served as a consultant for Alkermes, Lyndra and Sunovion. Dr. Procyshyn has been on the speaker's bureau and attended advisory board meetings for Janssen, Lundbeck, and Otsuka. Dr. Adebayo was on the advisory board of Janssen for a Long Acting Injectable Paliperidone palmitate in Nigeria. Janssen is not involved in Clozapine in Nigeria. Dr. Fountoulakis has received grants in the past, served as Publisher Copyright: {\textcopyright} 2022 Georg Thieme Verlag. All rights reserved.",

year = "2022",

month = mar,

day = "1",

doi = "10.1055/a-1625-6388",

language = "English",

volume = "55",

pages = "73--86",

journal = "Pharmakopsychiatrie und Neuropsychopharmakologie",

issn = "0176-3679",

publisher = "Georg Thieme Verlag",

number = "2",

}

TY - JOUR

T1 - An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

AU - De Leon, Jose

AU - Schoretsanitis, Georgios

AU - Smith, Robert L.

AU - Molden, Espen

AU - Solismaa, Anssi

AU - Seppälä, Niko

AU - Kopeček, Miloslav

AU - Švancer, Patrik

AU - Olmos, Ismael

AU - Ricciardi, Carina

AU - Iglesias-Garcia, Celso

AU - Iglesias-Alonso, Ana

AU - Spina, Edoardo

AU - Ruan, Can Jun

AU - Wang, Chuan Yue

AU - Wang, Gang

AU - Tang, Yi Lang

AU - Lin, Shih Ku

AU - Lane, Hsien Yuan

AU - Kim, Yong Sik

AU - Kim, Se Hyun

AU - Rajkumar, Anto P.

AU - González-Esquivel, Dinora F.

AU - Jung-Cook, Helgi

AU - Baptista, Trino

AU - Rohde, Christopher

AU - Nielsen, Jimmi

AU - Verdoux, Hélène

AU - Quiles, Clelia

AU - Sanz, Emilio J.

AU - De Las Cuevas, Carlos

AU - Cohen, Dan

AU - Schulte, Peter F.J.

AU - Ertuǧrul, Aygün

AU - Anll Yaǧcloǧlu, A. Elif

AU - Chopra, Nitin

AU - McCollum, Betsy

AU - Shelton, Charles

AU - Cotes, Robert O.

AU - Kaithi, Arun R.

AU - Kane, John M.

AU - Farooq, Saeed

AU - Ng, Chee H.

AU - Bilbily, John

AU - Hiemke, Christoph

AU - López-Jaramillo, Carlos

AU - McGrane, Ian

AU - Lana, Fernando

AU - Eap, Chin B.

AU - Arrojo-Romero, Manuel

AU - Rǎdulescu, Flavian

AU - Seifritz, Erich

AU - Every-Palmer, Susanna

AU - Bousman, Chad A.

AU - Bebawi, Emmanuel

AU - Bhattacharya, Rahul

AU - Kelly, Deanna L.

AU - Otsuka, Yuji

AU - Lazary, Judit

AU - Torres, Rafael

AU - Yecora, Agustin

AU - Motuca, Mariano

AU - Chan, Sherry K.W.

AU - Zolezzi, Monica

AU - Ouanes, Sami

AU - De Berardis, Domenico

AU - Grover, Sandeep

AU - Procyshyn, Ric M.

AU - Adebayo, Richard A.

AU - Kirilochev, Oleg O.

AU - Soloviev, Andrey

AU - Fountoulakis, Konstantinos N.

AU - Wilkowska, Alina

AU - Cubała, Wiesław J.

AU - Ayub, Muhammad

AU - Silva, Alzira

AU - Bonelli, Raphael M.

AU - Villagrán-Moreno, José M.

AU - Crespo-Facorro, Benedicto

AU - Temmingh, Henk

AU - Decloedt, Eric

AU - Pedro, Maria R.

AU - Takeuchi, Hiroyoshi

AU - Tsukahara, Masaru

AU - Gründer, Gerhard

AU - Sagud, Marina

AU - Celofiga, Andreja

AU - Ignjatovic Ristic, Dragana

AU - Ortiz, Bruno B.

AU - Elkis, Helio

AU - Pacheco Palha, António J.

AU - Llerena, Adrián

AU - Fernandez-Egea, Emilio

AU - Siskind, Dan

AU - Weizman, Abraham

AU - Masmoudi, Rim

AU - Mohd Saffian, Shamin

AU - Leung, Jonathan G.

AU - Buckley, Peter F.

AU - Marder, Stephen R.

AU - Citrome, Leslie

AU - Freudenreich, Oliver

AU - Correll, Christoph U.

AU - Müller, Daniel J.

N1 - Funding Information: reports consultation fees from Roche, Sunovion, Merck, Boehringer Ingelheim and Otsuka. He reports research support from Boehringer-Ingelheim, and GW Pharma. Dr. Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: AbbVie, Acadia, Alexza, Alkermes, Allergan, Angelini, Astellas, AstraZeneca, Avanir, Axsome, BioXcel, Boehringer Ingel-heim, Bristol-Myers Squibb, Cadent Therapeutics, Eisai, Eli Lilly, Forum, Genentech, Impel, Indivior, Intra-Cellular Therapies, Jans-sen, Jazz, Karuna, Lundbeck, Luye, Lyndra, Medavante-Prophase, Meiji, Merck, Medivation, Mylan, Neurocrine, NeuroRx, Novartis, Noven, Osmotica, Otsuka, Pfizer, Reckitt ?enckiser, Relmada, Re-viva, Sage, Shire, Sunovion, Takeda, Teva, University of Arizona, Valeant, Vanda, and one-o ? ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research. Dr. Freudenreich has the following financial relationship with a commercial interest to disclose (recipient SELF; content area SCHIZOPHRENIA): Alkermes – Research grant (to institution), consultant honoraria (Advisory Board); Avanir – Research grant (to institution); Janssen – Research grant (to institution), consultant honoraria (Advisory Board); Integral - Consultant honoraria; Neurocrine – Consultant honoraria (Advisory Board); Novartis – Consultant honoraria; Otsuka – Research grant (to institution); Roche – Consultant honoraria; Springer Verlag – Royalties (medical writer); Elsevier – Honoraria (medical editing); Global Medical Education – Honoraria (CME speaker and content developer); Medscape – Honoraria (CME speaker); American Psychiatric Association – Consultant honoraria (SMI Adviser); Wolters-Kluwer – Royalties (content developer); UpToDate – Royalties, honoraria (content developer and editor, including for a chapter on clozapine). Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Damitsa, Gedeon Richter, Hikma, IntraCellular Therapies, Janssen/ J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedIn-Cell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of LB Pharma. Dr. Müller reports he has been a co-investigator for two pharmacogenetic studies where genetic test kits were provided as an in-kind contribution by Myriad Neuroscience. He did not receive any payments or any equity, stocks, or options from any pharmacogenetic companies. He is also a co-inventor of two patents assessing risk for antipsychotic-induced weight gain (pending). Funding Information: Olmos, Ricciardi, Iglesias-Garcia, Iglesias-Alonso, Spina, Ruan, Chuan-Yue Wang, Gang Wang, Tang, Lin, Lane, Rajkumar, González-Esquivel, Jung-Cook, Baptista, Rohde, Nielsen, Verdoux, Quiles, Sanz, De las Cuevas, Cohen, Schulte, Chopra, McCollum, Shelton, Kaithi, Farooq, McGrane, Lana, Arrojo-Romero, Rădulescu, Every-Palmer, Bebawi, Bhattacharya, Otsuka, Lazary, Torres, Yecora, Motuca, Chan, Zolezzi, Ouanes, De Berardis, Grover, Kirilochev, Soloviev, Ayub, Silva, Bonelli, Temmingh, Decloedt, Pedro, Pacheco Palha, LLerena, Fernandez-Egea, Siskind, Masmoudi, Mohd Sa Can, Leung and ?uckley. In the last 3 years several authors report conflicts of interests. Dr. Seppälä is permanent medical advisor, received lecture fees and is an advisory board member from Viatris that markets clozapine in Finland and other European countries. Dr. Kopeček participated in speakers/advisory boards and lectured with the support of Angelini, Janssen Pharmaceuticals, Lundbeck and Richter Gedeon. Dr. Yong Sik Kim received grants, research support and honoraria from Janssen, Otsuka, Whan in Pharm and Bukwang Pharm (Sumitomo Dannipon Pharma). Dr. Se Hyun Kim received research grants from and/or served as a lecturer for Janssen, Eli Lilly, and Dongwha. Dr. Ertuğrul has received speaker’s honoraria from Abdi İbrahim Otsuka. Dr. Anıl Yağcıoğlu has received speaker’s honoraria and consulting fees from Janssen and Abdi İbrahim Otsuka. Dr. Cotes has received research funding from Otsuka, Lundbeck, Roche, Alkermes, and is a consultant for Saladax Biomedical. Dr. Kane reports personal fees from Alkermes, personal fees from Allergan, personal fees from Bristol-Myers Squibb, personal fees from IntraCellular Therapies, Janssen, Lundbeck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Sunovion, Takeda, Teva, outside-the-submitted work from LB Pharma, MedAvante and The Vanguard Research Group. Dr. Ng had served as consultant for Grunbiotics, Lundbeck, Servier, and Janssen-Cilag, and received research speaker honoraria from Servier, Janssen-Cilag and Pfizer.IMcG received royalties from Hogrefe Publishing Corp. T.L. Dr. Bilbily is supported by the National Institute on Drug Abuse training grant 5T32DA007261-30 (MPI). Dr. Hiemke received speaker’s honoraria from Otsuka. Dr. López-Jaramillo reports financial support for research from Financial support from the National Institute of Mental Health, USA, MinCiencias, Colombia and the Universidad de An-tioquia, Colombia. Dr. Eap received honoraria for conferences or teaching CME courses from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Vifor-Pharma, and Zeller. Dr. Seifritz has received honoraria from Schwabe GmbH for educational lectures. He has further received educational grants and consulting fees from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Recordati, Vifor, Sunovion, and Mepha. Dr. Bousman is a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Phar-macogene Variation Consortium (PharmVar). Dr. Kelly has served as a consultant for Alkermes, Lyndra and Sunovion. Dr. Procyshyn has been on the speaker's bureau and attended advisory board meetings for Janssen, Lundbeck, and Otsuka. Dr. Adebayo was on the advisory board of Janssen for a Long Acting Injectable Paliperidone palmitate in Nigeria. Janssen is not involved in Clozapine in Nigeria. Dr. Fountoulakis has received grants in the past, served as Publisher Copyright: © 2022 Georg Thieme Verlag. All rights reserved.

PY - 2022/3/1

Y1 - 2022/3/1

N2 - 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.

AB - 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.

KW - American continental ancestry group

KW - Asian continental ancestry group

KW - CYP1A2

KW - European continental ancestry group

KW - Native

KW - clozapine/adverse effects

KW - clozapine/blood

KW - clozapine/metabolism

KW - clozapine/therapeutic use

KW - clozapine/toxicity

KW - drug labeling

KW - infection

KW - inflammation

KW - mortality/drug effects

KW - sex

KW - smoking.

UR - http://www.scopus.com/inward/record.url?scp=85122150966&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85122150966&partnerID=8YFLogxK

U2 - 10.1055/a-1625-6388

DO - 10.1055/a-1625-6388

M3 - Review article

C2 - 35052001

AN - SCOPUS:85122150966

SN - 0176-3679

VL - 55

SP - 73

EP - 86

JO - Pharmakopsychiatrie und Neuropsychopharmakologie

JF - Pharmakopsychiatrie und Neuropsychopharmakologie

IS - 2

ER -