Body mass index as a determinant of clozapine plasma concentrations: A pharmacokinetic-based hypothesis

Kuzin, Maxim; Haen, Ekkehard; Hiemke, Christoph; Bochon, Benjamin; Bochon, Karolina; Gründer, Gerhard; Paulzen, Michael; Schoretsanitis, Georgios

doi:10.1177/0269881120985166

Cited by 18 publications

(10 citation statements)

References 52 publications

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“…The pharmacokinetic variables that may influence clozapine metabolism including DDIs, obesity, inflammation, geriatric age, and pregnancy have been reviewed in Supplementary Box S3 1 21 29 40 56 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 .…”

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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“…Indeed, 84% of the current TDM population were overweight (BMI > 25 kg/m 2 ), while 54% were obese (BMI > 30 kg/m 2 ). It has recently been demonstrated that all aspects of clozapine pharmacokinetics (absorption, distribution, metabolism and excretion) are perturbed in overweight and obese individuals [32], a phenomenon that is observed for many drugs [33,34]. Given the high propensity for clozapine to induce metabolic disturbances that result in profound weight gain [35,36], consideration of the potential impact of on-treatment weight gain on long term clozapine exposure warrants consideration.…”

Section: Discussionmentioning

confidence: 99%

Combining Therapeutic Drug Monitoring and Pharmacokinetic Modelling Deconvolutes Physiological and Environmental Sources of Variability in Clozapine Exposure

et al. 2021

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Background: Clozapine is a key antipsychotic drug for treatment-resistant schizophrenia but exhibits highly variable pharmacokinetics and a propensity for serious adverse effects. Currently, these challenges are addressed using therapeutic drug monitoring (TDM). This study primarily sought to (i) verify the importance of covariates identified in a prior clozapine population pharmacokinetic (popPK) model in the absence of environmental covariates using physiologically based pharmacokinetic (PBPK) modelling, and then to (ii) evaluate the performance of the popPK model as an adjunct or alternative to TDM-guided dosing in an active TDM population. Methods: A popPK model incorporating age, metabolic activity, sex, smoking status and weight was applied to predict clozapine trough concentrations (Cmin) in a PBPK-simulated population and an active TDM population comprising 142 patients dosed to steady state at Flinders Medical Centre in Adelaide, South Australia. Post hoc analyses were performed to deconvolute the impact of physiological and environmental covariates in the TDM population. Results: Analysis of PBPK simulations confirmed age, cytochrome P450 1A2 activity, sex and weight as physiological covariates associated with variability in clozapine Cmin (R2 = 0.7698; p = 0.0002). Prediction of clozapine Cmin using a popPK model based on these covariates accounted for <5% of inter-individual variability in the TDM population. Post hoc analyses confirmed that environmental covariates accounted for a greater proportion of the variability in clozapine Cmin in the TDM population. Conclusions: Variability in clozapine exposure was primarily driven by environmental covariates in an active TDM population. Pharmacokinetic modelling can be used as an adjunct to TDM to deconvolute sources of variability in clozapine exposure.

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“…38 In 586 Asians, <1% were PMs due to obesity. 33 Cross-sectional clozapine TDM studies 39,40 also suggest that metabolism and obesity ↓ clozapine metabolism. Obesity ↓ metabolism of other CYP1A2 drugs.…”

Section: Supplementary Table 1 the Need For An Open-minded Readermentioning

confidence: 99%

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

León

2023

Psychiatry Investig

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This review article argues against trusting standard clozapine references, including the US package insert, because they do not include advances in the sciences of pharmacokinetics and pharmacovigilance and ignore the effects of ethnic ancestry on therapeutic dosing. The minimum therapeutic dose leading to the minimum therapeutic concentration of 350 ng/mL in serum/plasma can be used to compare individuals/groups with treatment-resistant schizophrenia. The US clozapine package insert recommends targeting doses of 300-450 mg/day and, subsequently, increments of up to 100 mg with a maximum dose of 900 mg/day. Ethnic ancestry is defined by DNA ancestry group. Asians (people with ancestry ranging from Pakistan to Japan) and Indigenous Americans are similar in clozapine dosing; their average clozapine minimum therapeutic dose ranged from 166 mg/day (female non-smokers) to 270 mg/day (male smokers). For those with European ancestry, average clozapine minimum therapeutic doses ranged from 236 mg/day (female non-smokers) to 368 mg/day (male smokers). Based on limited studies, Black (African sub-Saharan ancestry) patients may be treated with typical US doses (300-600 mg/day), assuming no poor metabolism (PM) status. Ancestry's impact on clozapine lethality in four countries is discussed (two countries with highly homogenous populations, Denmark and Japan, and two countries with increasingly heterogenous populations due to immigration, Australia and the UK). An international guideline with 104 authors from 50 countries/regions was recently published, providing 6 personalized clozapine titration schedules for adult inpatients (3 ancestry groups and PM/non-PM schedules) and recommending c-reactive protein monitoring at baseline and weekly for 4 weeks.

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Body mass index as a determinant of clozapine plasma concentrations: A pharmacokinetic-based hypothesis

Cited by 18 publications

References 52 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

Combining Therapeutic Drug Monitoring and Pharmacokinetic Modelling Deconvolutes Physiological and Environmental Sources of Variability in Clozapine Exposure

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

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