Impact of CYP1A2, CYP2C19, and CYP2D6 genotype- and phenoconversion-predicted enzyme activity on clozapine exposure and symptom severity

Lesche, Dorothea; Mostafa, Sam; Everall, Ian; Pantelis, Christos; Bousman, Chad

doi:10.1038/s41397-019-0108-y

Cited by 51 publications

(69 citation statements)

References 41 publications

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“…On the other hand, lower clozapine levels were observed with CYP3A4 inducers like phenobarbital [64] and carbamazepine [67]. Esomeprazole [59] and minocycline [68] have explained the variability in clozapine concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…In literature, the majority of the studies have found significant effects of genetic variations in CYP1A2 on clozapine metabolism and plasma concentrations [30,36,[54][55][56][57], as well as side effects [58]. CYP1A2 activity scores corrected for known inducers and inhibitors were associated with the dose-adjusted clozapine level [59]. Association could not be found in some studies [60,61].…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics of Clozapine: A Systematic Review

Albitar

Harun

Zainal

et al. 2020

BioMed Research International

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Background and Objective. Clozapine is a second-generation antipsychotic drug that is considered the most effective treatment for refractory schizophrenia. Several clozapine population pharmacokinetic models have been introduced in the last decades. Thus, a systematic review was performed (i) to compare published pharmacokinetics models and (ii) to summarize and explore identified covariates influencing the clozapine pharmacokinetics models. Methods. A search of publications for population pharmacokinetic analyses of clozapine either in healthy volunteers or patients from inception to April 2019 was conducted in PubMed and SCOPUS databases. Reviews, methodology articles, in vitro and animal studies, and noncompartmental analysis were excluded. Results. Twelve studies were included in this review. Clozapine pharmacokinetics was described as one-compartment with first-order absorption and elimination in most of the studies. Significant interindividual variations of clozapine pharmacokinetic parameters were found in most of the included studies. Age, sex, smoking status, and cytochrome P450 1A2 were found to be the most common identified covariates affecting these parameters. External validation was only performed in one study to determine the predictive performance of the models. Conclusions. Large pharmacokinetic variability remains despite the inclusion of several covariates. This can be improved by including other potential factors such as genetic polymorphisms, metabolic factors, and significant drug-drug interactions in a well-designed population pharmacokinetic model in the future, taking into account the incorporation of larger sample size and more stringent sampling strategy. External validation should also be performed to the previously published models to compare their predictive performances.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Clozapine: A Systematic Review

Albitar

Harun

Zainal

et al. 2020

BioMed Research International

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“…The pharmacogenomic machinery is composed by a network of gene clusters coding for proteins and enzymes responsible for drug targeting and processing as well as critical components of the epigenetic machinery that regulate gene expression [60,61]. The pharmagenes involved in the pharmacogenomic response to drugs can be classified into five major categories: (i) Pathogenic genes (Table 1) which are associated with disease pathogenesis [62]; (ii) mechanistic genes coding for components of enzymes, receptor subunits, transmitters, and messengers associated with the mechanism of action of drugs; (iii) metabolic genes of different categories that encode phase I-II reaction enzymes responsible for drug metabolism.…”

Section: The Pharmacogenomic Machinerymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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“…In addition, the DPWG guidelines recommend reductions in the starting dose for pimozide and zuclopenthixol among CYP2D6 IMs, while for UMs they recommend the use of an alternative drug or titration to the maximum dose for haloperidol, risperidone, and zuclopenthixol. Of note, the FDA product label for clozapine suggest CYP2D6 PMs may require a dose reduction, despite CYP2D6's minor role (6 %) in the metabolism of clozapine [33], and a recent study that showed CYP2D6 genotype-predicted enzyme activity explained a minimal amount of the variance (3 %-7 %) in dose-adjusted clozapine levels and psychotic symptom severity [34]. In addition, the FDA product label for pimozide states CYP2D6 genetic testing should be performed if doses above 0.05 ▶Table 1 Actionable pharmacogenetic guidelines and product labels by antidepressants.…”

Section: Guidelinesmentioning

confidence: 99%

Review and Consensus on Pharmacogenomic Testing in Psychiatry

et al. 2020

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The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.

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Impact of CYP1A2, CYP2C19, and CYP2D6 genotype- and phenoconversion-predicted enzyme activity on clozapine exposure and symptom severity

Cited by 51 publications

References 41 publications

Population Pharmacokinetics of Clozapine: A Systematic Review

Population Pharmacokinetics of Clozapine: A Systematic Review

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Review and Consensus on Pharmacogenomic Testing in Psychiatry

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