Establishing the characteristics of an effective pharmacogenetic test for clozapine induced agranulocytosis

Verbelen, Moira; Collier, David A.; Cohen, Dan; MacCabe, James H.; Lewis, Cathryn M.

doi:10.1101/010900

Cited by 3 publications

(3 citation statements)

References 40 publications

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“…The proposed test of HLA-DQB1 6672G > C has high specifi city but low sensitivity, and fails to reduce the agranulocytosis risk in the LR group to a point that monitoring could be reduced or ceased (Verbelen et al 2014 ). Candidate gene studies have failed to identify a strong, replicated genetic variant that substantially increases risk of clozapine-induced agranulocytosis.…”

Section: Pharmacogenetics Of Clozapine-induced Agranulocytosismentioning

confidence: 91%

Pharmacogenetics

Jain¹

2015

Textbook of Personalized Medicine

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Pharmacogenetics, a term recognized in pharmacology in the pre-genomic era, is the study of infl uence of genetic factors on action of drugs as opposed to genetic causes of disease. Now it is the study of the linkage between the individual's genotype and the individual's ability to metabolize a foreign compound. The pharmacological effect of a drug depends on pharmacodynamics (interaction with the target or the site of action) and pharmacokinetics (absorption, distribution and metabolism). It also covers the infl uence of various factors on these processes. Drug metabolism is one of the major determinants of drug clearance and the factor that is most often responsible for interindividual differences in pharmacokinetics. Pharmacogenetics links genotype and phenotype as shown in Fig. 4.1 .The differences in response to medications are often greater among members of a population than they are within the same person or between monozygotic twins at different times. The existence of large population differences with small intrapatient variability is consistent with inheritance as a determinant of drug response. It is estimated that genetics can account for 20-95 % of variability in drug disposition and effects. Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the effi cacy and toxicity of many medications.Although interindividual variations in drug response result from effects of age, sex, disease or drug interactions, genetic factors represent an important infl uence in drug response and effi cacy and remain constant throughout life. This has led to the recognition of the discipline "pharmacogenetics" since the 1950s, which can be viewed an as integration of gene profi ling and pharmaceutical chemistry. From this initial defi nition, the scope has broadened so that it overlaps with pharmacogenomics (see Chap. 5 ).

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Section: Pharmacogenetics Of Clozapine-induced Agranulocytosismentioning

confidence: 91%

Pharmacogenetics

Jain¹

2015

Textbook of Personalized Medicine

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“…Whilst clozapine itself is not directly toxic to neutrophils its metabolites may be (5). Genetic linkage studies suggest both immune and anion transporter gene related mechanisms (6-9) but are not sufficiently predictive to be clinically useful and have predominantly examined European populations, so limiting applicability in other populations (10). CIN and CIA remain idiosyncratic, unpredictable type B adverse drug reactions (ADR).…”

Section: Mechanisms Of Cin and Ciamentioning

confidence: 99%

Clozapine Re-Challenge and Initiation Despite Neutropenia and Outcomes from 14 Patients

Silva

Higgins

Hammer

et al. 2019

Preprint

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Objective: Clozapine remains the most effective intervention for treatment resistant schizophrenia. But its use is limited because of the risk of neutropenia and agranulocytosis. In the absence of effective alternatives its use after blood dyscrasias is possible. Methods: A case series of 14 male patients with treatment resistant schizophrenia treated with clozapine despite previous episodes of neutropenia between 2006 and 2015 is presented. Data were collected during 2015 and 2019. Using routinely collected clinical data we describe the patient characteristics, causes of neutropenia, the strategies used and outcomes. Results: Previous neutropaenia was due to varying aetiologies: benign ethnic neutropaenia; clozapine induced; other medication; autoimmune. A range of risk mitigation strategies were used to prevent neutropaenia on clozapine rechallenge: G-CSF; lithium; watch and wait. There were no serious adverse events associated with clozapine or risk mitigation treatments. At follow up during 2019, half of the original 14 patients had improved sufficiently to transfer to conditions of lesser security. Conclusion: With careful planning and monitoring, taking into account what is known about neutrophil biology, clozapine can be successfully reinitiated following CIN or in the face of preexisting neutropenia resulting in significant benefits for patients.

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“…This is because the discovery of reliable genetic markers for CIA could contribute to the development of a predictive pharmacogenomic test to stratify patients based on risk. Patients identified as low risk will be less susceptible to developing CIA and can safely use clozapine with relaxed hematological monitoring, whereas those identified as high risk for developing CIA can undergo close, routine hematological monitoring or be considered for alternate treatments [23]. The development of such a clinical decision-making tool could minimize the risk and incidence of CIA, reduce costs associated with frequent hematological monitoring, and optimize treatment outcomes for TRS patients.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis

et al. 2022

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Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20–15.80, pcorrected = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.

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Establishing the characteristics of an effective pharmacogenetic test for clozapine induced agranulocytosis

Abstract: Clozapine is the only evidence-based therapy for treatment resistant schizophrenia, but it induces agranulocytosis, a rare but potentially fatal haematological adverse reaction, in less than 1% of users.

Cited by 3 publications

References 40 publications

Pharmacogenetics

Pharmacogenetics

Clozapine Re-Challenge and Initiation Despite Neutropenia and Outcomes from 14 Patients

Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis

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