Challenges and lessons learned from clinical pharmacogenetic implementation of multiple gene–drug pairs across ambulatory care settings

Cicali, Emily J.; Weitzel, Kristin; Elsey, Amanda R.; Orlando, Frank A.; Vinson, Michelle; Mosley, Scott A.; Smith, D. Max; Davis, Richard H.; Drum, Lori; Estores, David; Franciosi, James P.; Hagen, Melanie; Jerkins, Gabriel; Mercado, Elvira; Nainaparampil, Jaison; Padrón, Adaixa; Rosenberg, Eric I.; Wright, Ashleigh; Schmidt, Siegfried; Mathews, Carol A.; Cavallari, Larisa H.; Johnson, Julie A.

doi:10.1038/s41436-019-0500-7

Cited by 58 publications

(70 citation statements)

References 38 publications

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“…This cytochrome P450 enzyme is known for its genetic variability with about 100 different alleles [23] resulting in the phenotypes of poor, intermediate, normal, and ultra-rapid metabolizer (UM) with a prevalence of 0.4-5.4%, 0.4-11%, 67-90%, and 1-21%, respectively [24]. Moreover, CYP2D6 is known to be involved in the metabolism of a wide range of commonly used drugs [25] including SSRIs [26], opioids [27][28][29], and tamoxifen [30]. The second most cited biomarker in the Swiss DLs was CYP2C19.…”

Section: Discussionmentioning

confidence: 99%

“…The second most cited biomarker in the Swiss DLs was CYP2C19. This enzyme also affects a large number of drugs [25] including SSRIs [26,29], opioids [29], and in particular the bioactivation of clopidogrel [31]. However, none of the Swiss DL contained the biomarker ABCB1, although the Swiss guideline on the treatment of unipolar depressive episodes recommends to test for selected genetic variants of ABCB1 (P-Glycoprotein) in patients taking antidepressants [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

“…Although ABCB1 was not mentioned in the Swiss DLs, the anatomic group N (nervous system) dominated when analyzing PGx levels per anatomic group. This group contains antiepileptics (carbamazepine [35][36][37], oxacarbazepine [38], phenytoin [39,40]), antidepressants such as SSRIs [29], or analgesics such as opioids [29]. The anatomic group N relates to various drugs where treatment is associated with more difficulties (e.g., therapy failure) compared to therapies of other anatomic groups.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacogenetic information in Swiss drug labels – a systematic analysis

et al. 2020

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Implementation of pharmacogenetics (PGx) and individualization of drug therapy is supposed to obviate adverse drug reactions or therapy failure. Health care professionals (HCPs) use drug labels (DLs) as reliable information about drugs. We analyzed the Swiss DLs to give an overview on the currently available PGx instructions. We screened 4306 DLs applying natural language processing focusing on drug metabolism (pharmacokinetics) and we assigned PGx levels following the classification system of PharmGKB. From 5979 hits, 2564 were classified as PGx-relevant affecting 167 substances. 55% (n = 93) were classified as “actionable PGx”. Frequently, PGx information appeared in the pharmacokinetics section and in DLs of the anatomic group “nervous system”. Unstandardized wording, appearance of PGx information in different sections and unclear instructions challenge HCPs to identify and interpret PGx information and translate it into practice. HCPs need harmonization and standardization of PGx information in DLs to personalize drug therapies and tailor pharmaceutical care.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pharmacogenetic information in Swiss drug labels – a systematic analysis

et al. 2020

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“…In contrast, when CYP2D6 metabolizes a drug to its active form, such as with codeine to morphine, phenoconversion can reduce drug effectiveness. It has been suggested that consideration of both CYP2D6 genotype along with CYP2D6 drug interactions to infer the CYP2D6 clinical phenotype is a preferred approach for precision medicine …”

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confidence: 99%

A Scoping Review of the Evidence Behind Cytochrome P450 2D6 Isoenzyme Inhibitor Classifications

Cicali

Smith

Duong

et al. 2020

Clin Pharma and Therapeutics

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The US Food and Drug Administration (FDA) lists 22 medications as clinical inhibitors of cytochrome P450 2D6 isoenzyme, with classifications of strong, moderate, and weak. It is accepted that strong inhibitors result in nearly null enzymatic activity, but reduction caused by moderate and weak inhibitors is less well characterized. The objective was to identify if the classification of currently listed FDA moderate and weak inhibitors is supported by publicly available primary literature. We conducted a literature search and reviewed product labels for area under the plasma concentration‐time curve (AUC) fold‐changes caused by inhibitors in humans and identified 89 inhibitor–substrate pairs. Observed AUC fold‐change of the substrate was used to create an observed inhibitor classification per FDA‐defined AUC fold‐change thresholds. We then compared the observed inhibitor classification with the classification listed in the FDA Table of Inhibitors. We found 62% of the inhibitors within the pairs matched the listed FDA classification. We explored reasons for discordance and suggest modifications to the FDA table of clinical inhibitors for cimetidine, desvenlafaxine, and fluvoxamine.

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“…[9][10][11] These institutions contribute to expanding ev idence supporting clinical utility of pharmacogenetics and provide lessons learned, which can facilitate additional clin ical implementations. [12][13][14][15] Many institutions have started with cardiology, largely in the inpatient setting, when establishing a pharmacogenetic 1 MedStar Health, Columbia, Maryland, USA; 2 Georgetown University Medical Center, Washington, DC, USA; 3 MedStar Georgetown University Hospital, Washington, DC, USA; 4 MedStar Union Memorial Hospital, Baltimore, Maryland, USA; 5 MedStar Washington Hospital Center, Washington, DC, USA; 6 MedStar Cardiology Associates, LLC, Leonardtown, Maryland, USA. *Correspondence: Sandra M. Swain (sms248@georgetown.edu) Received: November 1, 2019; accepted: November 17, 2019. doi:10.1111/cts.12748…”

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confidence: 99%

Pharmacogenetics in Practice: Estimating the Clinical Actionability of Pharmacogenetic Testing in Perioperative and Ambulatory Settings

Smith

Peshkin

Springfield

et al. 2020

Clinical Translational Sci

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Most literature describing pharmacogenetic implementations are within academic medical centers and use single‐gene tests. Our objective was to describe the results and lessons learned from a multisite pharmacogenetic pilot that utilized panel‐based testing in academic and nonacademic settings. This was a retrospective analysis of 667 patients from a pilot in 4 perioperative and 5 outpatient cardiology clinics. Recommendations related to 12 genes and 65 drugs were classified as actionable or not actionable. They were ascertained from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and US Food and Drug Administration (FDA) labeling. Patients displayed a high prevalence of actionable results (88%, 99%) and use of medications (28%, 46%) with FDA or CPIC recommendations, respectively. Sixteen percent of patients had an actionable result for a current medication per CPIC compared with 5% per FDA labeling. A systematic approach by a health system may be beneficial given the quantity and diversity of patients affected.

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Challenges and lessons learned from clinical pharmacogenetic implementation of multiple gene–drug pairs across ambulatory care settings

Cited by 58 publications

References 38 publications

Pharmacogenetic information in Swiss drug labels – a systematic analysis

Pharmacogenetic information in Swiss drug labels – a systematic analysis

A Scoping Review of the Evidence Behind Cytochrome P450 2D6 Isoenzyme Inhibitor Classifications

Pharmacogenetics in Practice: Estimating the Clinical Actionability of Pharmacogenetic Testing in Perioperative and Ambulatory Settings

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