Quantifying the Impact of Phenoconversion on Medications With Actionable Pharmacogenomic Guideline Recommendations in an Acute Aged Persons Mental Health Setting

Mostafa, Sam; Polasek, Thomas M.; Sheffield, Leslie J.; Huppert, David; Kirkpatrick, Carl M.

doi:10.3389/fpsyt.2021.724170

Cited by 18 publications

(27 citation statements)

References 33 publications

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“…Drug-induced phenoconversion is common in older adults with polypharmacy being treated for MDD, as many antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs]) are metabolized by or interact with CYP2C19 and/or CYP2D6 enzymes [ 12 , 13 , 14 ]. For example, drug-induced phenoconversion can be observed if a patient identified as a CYP2C19 normal metabolizer (NM) takes fluoxetine, a CYP2C19 inhibitor, causing the observed phenotype to resemble a PM for the victim drug.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Performing a Medication Safety Review Assisted by Pharmacogenomics to Explain a Prescribing Cascade Resulting in a Patient Fall

Russell¹,

Arwood

Toro-Pagán³

et al. 2023

Medicina

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Pharmacotherapy for major depressive disorder (MDD) typically consists of trial-and-error and clinician preference approaches, where patients often fail one or more antidepressants before finding an optimal regimen. Pharmacogenomics (PGx) can assist in prescribing appropriate antidepressants, thereby reducing the time to MDD remission and occurrence of adverse drug events. Since many antidepressants are metabolized by and/or inhibit cytochrome P450 enzymes (e.g., CYP2C19 or CYP2D6), drug-induced phenoconversion is common in patients on antidepressant combinations. This condition influences the interpretation of a patient’s PGx results, overall risk of ineffective/adverse medication response due to multi-drug interactions, and the recommendations. This complex case describes a patient with MDD, generalized anxiety disorder, and chronic pain who experienced a fall due to excessive sedation following a prescribing cascade of fluoxetine, bupropion, and doxepin. These antidepressants delivered a significant additive sedative effect and interacted with the patient’s hydrocodone, potentially contributing to uncontrolled pain, upward dose titration of hydrocodone, and a higher overall sedative burden. The PGx results and drug-induced phenoconversion described in this case report explain the patient’s excessive sedation and possibly ineffective/toxic antidepressant and opioid treatment. This case report also illustrates how a more timely multi-drug interaction assessment (preferably in conjunction with preemptive PGx testing) may have informed a different prescribing pattern, reduced/avoided a prescribing cascade, and potentially prevented a drug-related fall.

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Section: Discussionmentioning

confidence: 99%

Case Report: Performing a Medication Safety Review Assisted by Pharmacogenomics to Explain a Prescribing Cascade Resulting in a Patient Fall

Russell¹,

Arwood

Toro-Pagán³

et al. 2023

Medicina

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“…As of today, data on the relevance of PC for CYP2C19 are missing. One study described a decrease in CYP2C19 NM and an increase in IM when considering PC; however, the authors did not report statistical significance [13]. Unlike CYP2D6, different methods are available for CYP2C19 to correct for PC effects, taking into account the presence of an inducer or a moderate or strong inhibitor [7,15,16].…”

Section: Introductionmentioning

confidence: 99%

The Relevance of Integrating CYP2C19 Phenoconversion Effects into Clinical Pharmacogenetics

Scherf-Clavel,

Weber,

Unterecker

et al. 2024

Pharmacopsychiatry

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Introduction CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status. Methods Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PCBousman, PCHahn&Roll) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine. Results There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram. Discussion PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.

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Section: Introductionmentioning

confidence: 99%

“…Polypharmacy may complicate the interpretation of the PGx results, especially when co-administered medications share the same metabolic pathway and affect the drug-induced phenoconversion [ 4 ]. Phenoconversion occurs when nongenetic factors, such as concomitant medications, age, and comorbidities, alter the genotype-predicted phenotype of drug-metabolizing enzymes [ 4 ]. Assessing for the drug-induced phenoconversion, as opposed to solely relying on genetic results, allows for a more accurate prediction of medication response and an optimization of patient outcomes [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Phenoconversion occurs when nongenetic factors, such as concomitant medications, age, and comorbidities, alter the genotype-predicted phenotype of drug-metabolizing enzymes [ 4 ]. Assessing for the drug-induced phenoconversion, as opposed to solely relying on genetic results, allows for a more accurate prediction of medication response and an optimization of patient outcomes [ 4 ]. The clinical decision support systems (CDSSs) can help to identify drug–drug interactions (DDIs), DGIs, DDGIs, and drug-induced phenoconversion [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenomics and Drug-Induced Phenoconversion Informed Medication Safety Review in the Management of Pain Control and Quality of Life: A Case Report

Muhn¹,

Amin²,

Bardolia³

et al. 2022

JPM

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Utilizing pharmacogenomics (PGx) and integrating drug-induced phenoconversion to guide opioid therapies could improve the treatment response and decrease the occurrence of adverse drug events. Genetics contribute to the interindividual differences in opioid response. The purpose of this case report highlights the impact of a PGx-informed medication safety review, assisted by a clinical decision support system, in mitigating the drug–gene and drug–drug–gene interactions (DGI and DDGI, respectively) that increase the risk of an inadequate drug response and adverse drug events (ADEs). This case describes a 69-year-old female who was referred for PGx testing for uncontrolled chronic pain caused by osteoarthritis and neuropathy. The clinical pharmacist reviewed the PGx test results and medication regimen and identified several (DGIs and DDGIs, respectively) at Cytochrome P450 (CYP) 2C19 and CYP2D6. The recommendations were to: (1) switch tramadol to buprenorphine transdermal patch, an opioid with lower potential for ADEs, to mitigate a CYP2D6 DDGI; (2) gradually discontinue amitriptyline to alleviate the risk of anticholinergic side effects, ADEs, and multiple DDGIs; and (3) optimize the pregabalin. The provider and the patient agreed to implement these recommendations. Upon follow-up one month later, the patient reported an improved quality of life and pain control. Following the amitriptyline taper, the patient experienced tremors in the upper and lower extremities. When the perpetrator drug, omeprazole, was stopped, the metabolic capacity was no longer impeded; the patient experienced possible amitriptyline withdrawal symptoms due to the rapid withdrawal of amitriptyline, which was reinitiated and tapered off more slowly. This case report demonstrates a successful PGx-informed medication safety review that considered drug-induced phenoconversion and mitigated the risks of pharmacotherapy failure, ADEs, and opioid misuse.

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Quantifying the Impact of Phenoconversion on Medications With Actionable Pharmacogenomic Guideline Recommendations in an Acute Aged Persons Mental Health Setting

Cited by 18 publications

References 33 publications

Case Report: Performing a Medication Safety Review Assisted by Pharmacogenomics to Explain a Prescribing Cascade Resulting in a Patient Fall

Case Report: Performing a Medication Safety Review Assisted by Pharmacogenomics to Explain a Prescribing Cascade Resulting in a Patient Fall

The Relevance of Integrating CYP2C19 Phenoconversion Effects into Clinical Pharmacogenetics

Pharmacogenomics and Drug-Induced Phenoconversion Informed Medication Safety Review in the Management of Pain Control and Quality of Life: A Case Report

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