The Impact of Smoking, Sex, Infection, and Comedication Administration on Oral Olanzapine: A Population Pharmacokinetic Model in Chinese Psychiatric Patients

Zang, Yan-Nan; Dong, Fang; Li, An-Ning; Wang, Chuanyue; Guo, Gui-Xin; Wang, Qian; Zhang, Yanfang; Zhang, Lei; Leon, José de; Ruan, Changgeng

doi:10.1007/s13318-021-00673-5

Cited by 20 publications

(26 citation statements)

References 102 publications

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“…Supplementary Box S4 50 62 68 80 81 82 83 84 85 86 87 provides a detailed review of the limited available data on the influence of genetics and ancestry on clozapine metabolism and CYP1A2 activity. There are five main DNA ancestry groups 80 : African, European (and Western Asian), Asian (defined by the FDA as people whose ancestry ranges geographically from Pakistan to Japan), Oceanian, and the original people from the Americas.…”

Section: Advances In Clozapine Pharmacokinetics Not Included In the U...mentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Advances In Clozapine Pharmacokinetics Not Included In the U...mentioning

confidence: 99%

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

et al. 2021

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“…Asians need lower olanzapine doses. 26 On the other hand, people of black ancestry (sub-Saharan Africans) may need higher olanzapine 27 and, possibly, clozapine doses. Moreover, higher clozapine dose requirements in African-American patients in the USA versus those of European ancestry may explain why US experts and the US package insert recommend 300–600 mg/day of clozapine, which is higher than the dosages used in Europe.…”

Section: International Clozapine Titration Guidelinementioning

confidence: 99%

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine

et al. 2022

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White blood cell (WBC) monitoring has reduced clozapine-treated patient deaths associated with agranulocytosis to a rarity. However, clozapine protocols and package inserts worldwide provide no instructions for preventing myocarditis or pneumonia during clozapine titrations. Prescribers worldwide are largely unaware of that. Meanwhile, as they worry about agranulocytosis, their clozapine-treated patients are at risk of dying from pneumonia or myocarditis. Consequently, an international guideline with 104 authors from 50 countries/regions was recently published to provide personalised clozapine titration schedules for adult inpatients. This forum article reviews pneumonia and myocarditis occurring during clozapine titration, as well as the three most innovative aspects of this new guideline: (1) personalised titration, (2) C reactive protein (CRP) measures, and (3) dose predictions based on blood levels. Clozapine metabolism is influenced by 3 levels of complexity: (1) ancestry groups, (2) sex-smoking subgroups, and (3) presence/absence of poor metabolizer status. These 3 groups of variables should determine the maintenance dose and speed of clozapine titration; they are summarised in a table in the full-text. The international clozapine titration guideline recommends measuring CRP levels simultaneously with WBC, at baseline and weekly at least for the first 4 weeks of titration, the highest risk period for clozapine-induced myocarditis.

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“…Since the polycyclic aromatic hydrocarbons in tobacco smoke mainly affect CYP1A2, most data on smoking behavior and changes in plasma concentration pertain to SGAs such as clozapine and olanzapine, which are CYP1A2 substrates. In general, smokers have lower serum levels of clozapine and olanzapine than non-smokers when treated with the same oral dose [33,67,[213][214][215][216][217][218][219]. Published reports document 20-40% lower mean serum clozapine concentrations in smokers (up to 14 cigarettes per day) compared with nonsmokers due to enzyme induction [67].…”

Section: Effects Of Smoking On Drug Levels Of Antipsychotic Drugs Metabolized Via Cyp1a2mentioning

confidence: 99%

“…When a patient stops smoking, dose reduction of clozapine of 30-50% is recommended [213,215]. In a Chinese study of 354 adult psychiatric patients, olanzapine elimination was increased 1.23-fold by smoking [214]; therefore, Tsuda et al suggest that the dose of olanzapine should be reduced by 30% in non-smokers compared with smokers to obtain an equivalent olanzapine concentration [213].…”

Section: Effects Of Smoking On Drug Levels Of Antipsychotic Drugs Metabolized Via Cyp1a2mentioning

confidence: 99%

“…Overall, blood levels are highly variable. In addition to smoking behavior and interindividual differences (e.g., genetic variations like a novel variant in the nuclear factor 1 B-type gene associated with reduced clozapine levels [220]) drug concentrations are also influenced by other factors such as age, gender, origin, and co-medication [214,215,[217][218][219]. However, previous research has demonstrated that, after clozapine dosage itself, smoking is the factor that most affects clozapine plasma concentration [67].…”

Section: Effects Of Smoking On Drug Levels Of Antipsychotic Drugs Metabolized Via Cyp1a2mentioning

confidence: 99%

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Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

et al. 2021

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Both inflammation and smoking can influence a drug’s pharmacokinetic properties, i.e., its liberation, absorption, distribution, metabolism, and elimination. Depending on, e.g., pharmacogenetics, these changes may alter treatment response or cause serious adverse drug reactions and are thus of clinical relevance. Antipsychotic drugs, used in the treatment of psychosis and schizophrenia, should be closely monitored due to multiple factors (e.g., the narrow therapeutic window of certain psychotropic drugs, the chronicity of most mental illnesses, and the common occurrence of polypharmacotherapy in psychiatry). Therapeutic drug monitoring (TDM) aids with drug titration by enabling the quantification of patients’ drug levels. Recommendations on the use of TDM during treatment with psychotropic drugs are presented in the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology; however, data on antipsychotic drug levels during inflammation or after changes in smoking behavior—both clinically relevant in psychiatry—that can aid clinical decision making are sparse. The following narrative review provides an overview of relevant literature regarding TDM in psychiatry, particularly in the context of second- and third-generation antipsychotic drugs, inflammation, and smoking behavior. It aims to spread awareness regarding TDM (most pronouncedly of clozapine and olanzapine) as a tool to optimize drug safety and provide patient-tailored treatment.

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The Impact of Smoking, Sex, Infection, and Comedication Administration on Oral Olanzapine: A Population Pharmacokinetic Model in Chinese Psychiatric Patients

Cited by 20 publications

References 102 publications

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

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

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

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