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

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish
Pages (from-to)73-86
Number of pages14
JournalPharmacopsychiatry
Volume55
Issue number2
DOIs
StatePublished - 1 Mar 2022

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.

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