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

de Leon, Jose; Schoretsanitis, Georgios; Smith, Robert L.; Molden, Espen; Solismaa, Anssi; Seppälä, Niko; Kopeček, Miloslav; Švancer, Patrik; Olmos, Ismael; Ricciardi, Carina; Iglesias-Garcia, Celso; Iglesias-Alonso, Ana; Spina, Edoardo; Ruan, Can-Jun; Wang, Chuan-Yue; Wang, Gang; Tang, Yi-Lang; Lin, Shih-Ku; Lane, Hsien-Yuan; Kim, Yong Sik; Kim, Se Hyun; Rajkumar, Anto P.; González-Esquivel, Dinora F.; Jung-Cook, Helgi; Baptista, Trino; Rohde, Christopher; Nielsen, Jimmi; Verdoux, Hélène; Quiles, Clelia; Sanz, Emilio J.; De Las Cuevas, Carlos; Cohen, Dan; Schulte, Peter F.J.; Ertuğrul, Aygün; Anıl Yağcıoğlu, A. Elif; Chopra, Nitin; McCollum, Betsy; Shelton, Charles; Cotes, Robert O.; Kaithi, Arun R.; Kane, John M.; Farooq, Saeed; Ng, Chee H.; Bilbily, John; Hiemke, Christoph; López-Jaramillo, Carlos; McGrane, Ian; Lana, Fernando; Eap, Chin B.; Arrojo-Romero, Manuel; Rădulescu, Flavian Ş.; Seifritz, Erich; Every-Palmer, Susanna; Bousman, Chad A.; Bebawi, Emmanuel; Bhattacharya, Rahul;...

Authors

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

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



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.

Journal Article Type Article
Acceptance Date Aug 23, 2021
Online Publication Date Dec 15, 2021
Publication Date Dec 15, 2021
Publicly Available Date Mar 29, 2024
Journal Pharmacopsychiatry
Print ISSN 0176-3679
Publisher Thieme Gruppe
Volume 55
Issue 02
Pages 73-86
DOI https://doi.org/10.1055/a-1625-6388
Keywords Pharmacology (medical), Psychiatry and Mental health, General Medicine
Publisher URL https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-1625-6388