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Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (20 April 2022) | Viewed by 42075

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Special Issue Editors

Dr. Charlotte Vermehren

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Guest Editor

Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark
Interests: polypharmacy; multimorbidity; medication review; deprescribing
Special Issues, Collections and Topics in MDPI journals

Dr. Niels Westergaard

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Guest Editor

University Colleges Absalon, Parkvej 190, 4700 Naestved, Denmark
Interests: drug consumption; cytochrome P450; polypharmacy; pharmacogenomics, drug–drug and drug‐gene interactions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Polypharmacy is a necessary and important aspect of drug treatment; however, it becomes a challenge when the medication risks outweigh the benefits for an individual patient. Drug–drug interactions and the introduction of prescribing cascades are common features of polypharmacy, which can lead to ineffectiveness and an increased risk of adverse drug reactions (ADR). Genes encoding CYP450 isozymes and other drug-related biomarkers have attracted considerable attention as targets for pharmacogenomic (PGx) testing due to their impact on drug metabolism and response. This Special Issue is devoted to exploring the status and initiatives taken to circumvent ineffectiveness of and increase in ADRs in polypharmacy patients. Specific areas include, but are not limited to, drug–drug interactions in the metabolism of drugs and consequences in therapeutic management, including PK- and PD-profiling; the application of PGx-based guidance and/or decision tools for drug–gene and drug–drug gene interactions; the development of drug interaction trackers dealing with these issues; drivers and barriers to overcoming these issues for successful implementation in the healthcare system and the cost-effectiveness of PGx-guided treatment. Focused medication reviews of the use, development, and application of deprescribing tools are also welcome. Finally, we also invite manuscripts describing new and innovative approaches to deal with the challenges of polypharmacy within the frame of this Special Issue.

Dr. Charlotte Vermehren
Dr. Niels Westergaard
Guest Editors

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Keywords

polypharmacy
drug–gene and drug–drug gene interactions
PGx based biomarkers in drug
metabolism and response
drug metabolism
pharmacokinetic and pharmacodynamic profiling and interactions
PGx-testing
deprescribing
cost-effectiveness of PGx-guided treatments

Published Papers (14 papers)

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Research

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16 pages, 987 KiB

Open AccessArticle

Clinical Impact of Functional CYP2C19 and CYP2D6 Gene Variants on Treatment with Antidepressants in Young People with Depression: A Danish Cohort Study

by Liv S. Thiele, Kazi Ishtiak-Ahmed, Janne P. Thirstrup, Esben Agerbo, Carin A. T. C. Lunenburg, Daniel J. Müller and Christiane Gasse

Pharmaceuticals 2022, 15(7), 870; https://doi.org/10.3390/ph15070870 - 14 Jul 2022

Cited by 12 | Viewed by 4968

Abstract

Background: The clinical impact of the functional CYP2C19 and CYP2D6 gene variants on antidepressant treatment in people with depression is not well studied. Here, we evaluate the utility of pharmacogenetic (PGx) testing in psychiatry by investigating the association between the phenotype status of the cytochrome P450 (CYP) 2C19/2D6 enzymes and the one-year risks of clinical outcomes in patients with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine. Methods: This study is a population-based cohort study of 17,297 individuals who were born between 1981 and 2005 with a depression diagnosis between 1996 and 2012. Using array-based single-nucleotide-polymorphism genotype data, the individuals were categorized according to their metabolizing status of CYP2C19/CYP2D6 as normal (NM, reference group), ultra-rapid- (UM), rapid- (RM), intermediate- (IM), or poor-metabolizer (PM). The outcomes were treatment switching or discontinuation, psychiatric emergency department contacts, and suicide attempt/self-harm. By using Poisson regression analyses, we have estimated the incidence rate ratios (IRR) with 95% confidence intervals (95% CI) that were adjusted for covariates and potential confounders, by age groups (<18 (children and adolescents), 19–25 (young adults), and 26+ years (adults)), comparing the outcomes in individuals with NM status (reference) versus the mutant metabolizer status. For statistically significant outcomes, we have calculated the number needed to treat (NNT) and the number needed to genotype (NNG) in order to prevent one outcome. Results: The children and adolescents who were using (es)citalopram with CYP2C19 PM status had increased risks of switching (IRR = 1.64 [95% CI: 1.10–2.43]) and suicide attempt/self-harm (IRR = 2.67 [95% CI; 1.57–4.52]). The young adults with CYP2C19 PM status who were using sertraline had an increased risk of switching (IRR = 2.06 [95% CI; 1.03–4.11]). The young adults with CYP2D6 PM status who were using fluoxetine had an increased risk of emergency department contacts (IRR = 3.28 [95% CI; 1.11–9.63]). No significant associations were detected in the adults. The NNG for preventing one suicide attempt/suicide in the children who were using (es)citalopram was 463, and the NNT was 11. Conclusion: The CYP2C19 and CYP2D6 PM phenotype statuses were associated with outcomes in children, adolescents, and young adults with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine, therefore indicating the utility of PGx testing, particularly in younger people, for PGx-guided antidepressant treatment. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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19 pages, 4493 KiB

Open AccessArticle

Use of an Electronic Medication Management Support System in Patients with Polypharmacy in General Practice: A Quantitative Process Evaluation of the AdAM Trial

by Robin Brünn, Dorothea Lemke, Jale Basten, Petra Kellermann-Mühlhoff, Juliane Köberlein-Neu, Christiane Muth, Marjan van den Akker and on behalf of the AdAM Study Group

Pharmaceuticals 2022, 15(6), 759; https://doi.org/10.3390/ph15060759 - 17 Jun 2022

Cited by 3 | Viewed by 2136

Abstract

Polypharmacy is associated with a risk of negative health outcomes. Potentially inappropriate medications, interactions resulting from contradicting medical guidelines, and inappropriate monitoring, all increase the risk. This process evaluation (PE) of the AdAM study investigates implementation and use of a computerized decision-support system (CDSS). The CDSS analyzes medication appropriateness by including claims data, and hence provides general practitioners (GPs) with full access to patients’ medical treatments. We based our PE on pseudonymized logbook entries into the CDSS and used the four dimensions of the Medical Research Council PE framework. Reach, which examines the extent to which the intended study population was included, and Dose, Fidelity, and Tailoring, which examine how the software was actually used by GPs. The PE was explorative and descriptive. Study participants were representative of the target population, except for patients receiving a high level of nursing care, as they were treated less frequently. GPs identified and corrected inappropriate prescriptions flagged by the CDSS. The frequency and intensity of interventions documented in the form of logbook entries lagged behind expectations, raising questions about implementation barriers to the intervention and the limitations of the PE. Impossibility to connect the CDSS to GPs’ electronic medical records (EMR) of GPs due to technical conditions in the German healthcare system may have hindered the implementation of the intervention. Data logged in the CDSS may underestimate medication changes in patients, as documentation was voluntary and already included in EMR. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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13 pages, 1542 KiB

Open AccessArticle

Exploration of Symptom Scale as an Outcome for Deprescribing: A Medication Review Study in Nursing Homes

by Dagmar Abelone Dalin, Sara Frandsen, Gitte Krogh Madsen and Charlotte Vermehren

Pharmaceuticals 2022, 15(5), 505; https://doi.org/10.3390/ph15050505 - 21 Apr 2022

Cited by 2 | Viewed by 1784

Abstract

The use of inappropriate medication is an increasing problem among the elderly, leading to hospitalizations, mortality, adverse effects, and lower quality of life (QoL). Deprescribing interventions (e.g., medication reviews (MRs)) have been examined as a possible remedy for this problem. In order to be able to evaluate the potential benefits and harms of a deprescribing intervention, quality of life (QoL) has increasingly been used as an outcome. The sensitivity of QoL measurements may, however, not be sufficient to detect a change in specific disease symptoms, e.g., a flair-up in symptoms or relief of side effects after deprescribing. Using symptom assessments as an outcome, we might be able to identify and evaluate the adverse effects of overmedication and deprescribing alike. The objective of this study was to explore whether symptom assessment is a feasible and valuable method of evaluating outcomes of MRs among the elderly in nursing homes. To the best of our knowledge, this has not been investigated before. We performed a feasibility study based on an experimental design and conducted MRs for elderly patients in nursing homes. Their symptoms were registered at baseline and at a follow-up 3 months after performing the MR. In total, 86 patients, corresponding to 68% of the included patients, received the MR and completed the symptom questionnaires as well as the QoL measurements at baseline and follow-up, respectively. Forty-eight of these patients had at least one deprescribing recommendation implemented. Overall, a tendency towards the improvement of most symptoms was seen after deprescribing, which correlated with the tendencies observed for the QoL measurements. Remarkably, deprescribing did not cause a deterioration of symptoms or QoL, which might otherwise be expected for patients of this age group, of whom the health is often rapidly declining. In conclusion, it was found that symptom assessments were feasible among nursing home residents and resulted in additional relevant information about the potential benefits and harms of deprescribing. It is thus recommended to further explore the use of symptom assessment as an outcome of deprescribing interventions, e.g., in a controlled trial. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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13 pages, 2480 KiB

Open AccessArticle

Simple and Robust Detection of CYP2D6 Gene Deletions and Duplications Using CYP2D8P as Reference

by Jens Borggaard Larsen and Steffen Jørgensen

Pharmaceuticals 2022, 15(2), 166; https://doi.org/10.3390/ph15020166 - 28 Jan 2022

Cited by 1 | Viewed by 2961

Abstract

Genotyping of the CYP2D6 gene is the most commonly applied pharmacogenetic test globally. Significant economic interests have led to the development of a plurality of assays, available for almost any genotyping platform or DNA detection chemistry. Of all the genetic variants, copy number variations are particular difficult to detect by polymerase chain reaction. Here, we present two simple novel approaches for the identification of samples carrying either deletions or duplications of the CYP2D6 gene; by relative quantification using a singleplex 5′nuclease real-time PCR assay, and by high-resolution melting of PCR products. These methods make use of universal primers, targeting both the CYP2D6 and the reference gene CYP2D8P, which is necessary for the analysis. The assays were validated against a reference method using a large set of samples. The singleplex nature of the 5′nuclease real-time PCR ensures that the primers anneal with equal affinity to both the sequence of the CYP2D6 and the reference gene. This facilitates robust identification of gene deletions and duplications based on the cycle threshold value. In contrast, the high-resolution melting assay is an end-point PCR, where the identification relies on variations between the amount of product generated from each of the two genes. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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13 pages, 439 KiB

Open AccessArticle

Medicines Reconciliation in the Emergency Department: Important Prescribing Discrepancies between the Shared Medication Record and Patients’ Actual Use of Medication

by Tanja Stenholdt Andersen, Mia Nimb Gemmer, Hayley Rose Constance Sejberg, Lillian Mørch Jørgensen, Thomas Kallemose, Ove Andersen, Esben Iversen and Morten Baltzer Houlind

Pharmaceuticals 2022, 15(2), 142; https://doi.org/10.3390/ph15020142 - 26 Jan 2022

Cited by 5 | Viewed by 3466

Abstract

Medication reconciliation is crucial to prevent medication errors. In Denmark, primary and secondary care physicians can prescribe medication in the same electronic prescribing system known as the Shared Medication Record (SMR). However, the SMR is not always updated by physicians, which can lead to discrepancies between the SMR and patients’ actual use of medication. These discrepancies may compromise patient safety upon admission to the emergency department (ED). Here, we investigated (a) the occurrence of discrepancies, (b) factors associated with discrepancies, and (c) the percentage of patients accessible to a clinical pharmacist during pharmacy working hours. The study included all patients age ≥ 18 years who were admitted to the Hvidovre Hospital ED on three consecutive days in June 2020. The clinical pharmacists performed medicines reconciliation to identify prescribing discrepancies. In total, 100 patients (52% male; median age 66.5 years) were included. The patients had a median of 10 [IQR 7–13] medications listed in the SMR and a median of two [IQR 1–3.25] discrepancies. Factors associated with increased rate of prescribing discrepancies were age < 65 years, time since last update of the SMR ≥ 115 days, and patients’ self-dispensing their medications. Eighty-four percent of patients were available for medicines reconciliations during the normal working hours of the clinical pharmacist. In conclusion, we found that discrepancies between the SMR and patients’ actual medication use upon admission to the ED are frequent, and we identified several risk factors associated with the increased rate of discrepancies. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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12 pages, 272 KiB

Open AccessArticle

Genotyping for HLA Risk Alleles to Prevent Drug Hypersensitivity Reactions: Impact Analysis

by Lisanne E. N. Manson, Wilbert B. van den Hout and Henk-Jan Guchelaar

Pharmaceuticals 2022, 15(1), 4; https://doi.org/10.3390/ph15010004 - 21 Dec 2021

Cited by 4 | Viewed by 3834

Abstract

Human Leukocyte Antigen (HLA) variants can be a risk factor for developing potentially fatal drug hypersensitivity reactions. Our aim was to estimate the potential impact of genotyping for the HLA risk alleles incorporated in the Dutch Pharmacogenetics Working Group (DPWG) guidelines in The Netherlands. We estimated the number of hypersensitivity reactions and associated deaths that can be avoided annually by genotyping for these HLA risk alleles. Additionally, the cost-effectiveness was estimated. Nationwide implementation of genotyping HLA risk alleles before initiating drugs with an actionable drug–gene interaction can potentially save the life of seven allopurinol initiators and two flucloxacillin initiators each year in The Netherlands. Besides these deaths, 28 cases of abacavir hypersensitivity, 24 cases of allopurinol induced SCARs, 6 cases of carbamazepine induced DRESS and 22 cases of flucloxacillin induced DILI can be prevented. Genotyping HLA-B*5701 in abacavir initiators has a number needed to genotype of 31 to prevent one case of abacavir hypersensitivity and is cost-saving. Genotyping HLA-B*5801 in allopurinol initiators has a number needed to genotype of 1149 to prevent one case of SCAR but is still cost-effective. Genotyping before initiating antiepileptic drugs or flucloxacillin is not cost-effective. Our results confirm the need for mandatory testing of HLA-B*5701 in abacavir initiators, as indicated in the drug label, and show genotyping of HLA-B*5801 in allopurinol initiators should be considered. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

14 pages, 464 KiB

Open AccessArticle

Individualized versus Standardized Risk Assessment in Patients at High Risk for Adverse Drug Reactions (The IDrug Randomized Controlled Trial)–Never Change a Running System?

by Katja S. Just, Catharina Scholl, Miriam Boehme, Kathrin Kastenmüller, Johannes M. Just, Markus Bleckwenn, Stefan Holdenrieder, Florian Meier, Klaus Weckbecker and Julia C. Stingl

Pharmaceuticals 2021, 14(10), 1056; https://doi.org/10.3390/ph14101056 - 18 Oct 2021

Viewed by 2052

Abstract

The aim of this study was to compare effects of an individualized with a standardized risk assessment for adverse drug reactions to improve drug treatment with antithrombotic drugs in older adults. A randomized controlled trial was conducted in general practitioner (GP) offices. Patients aged 60 years and older, multi-morbid, taking antithrombotic drugs and at least one additional drug continuously were randomized to individualized and standardized risk assessment groups. Patients were followed up for nine months. A composite endpoint defined as at least one bleeding, thromboembolic event or death reported via a trigger list was used. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. In total, N = 340 patients were enrolled from 43 GP offices. Patients in the individualized risk assessment group met the composite endpoint more often than in the standardized group (OR 1.63 [95%CI 1.02–2.63]) with multiple adjustments. The OR was higher in patients on phenprocoumon treatment (OR 1.99 [95%CI 1.05–3.76]), and not significant on DOAC treatment (OR 1.52 [95%CI 0.63–3.69]). Pharmacogenenetic variants of CYP2C9, 2C19 and VKORC1 were not observed to be associated with the composite endpoint. The results of this study may indicate that the time point for implementing individualized risk assessments is of importance. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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14 pages, 483 KiB

Open AccessArticle

Comparison of Multidrug Use in the General Population and among Persons with Diabetes in Denmark for Drugs Having Pharmacogenomics (PGx) Based Dosing Guidelines

by Niels Westergaard, Lise Tarnow and Charlotte Vermehren

Pharmaceuticals 2021, 14(9), 899; https://doi.org/10.3390/ph14090899 - 3 Sep 2021

Cited by 2 | Viewed by 2537

Abstract

Background: This study measures the use of drugs within the therapeutic areas of antithrombotic agents (B01), the cardiovascular system (C), analgesics (N02), psycholeptics (N05), and psychoanaleptics (N06) among the general population (GP) in comparison to persons with diabetes in Denmark. The study focuses on drugs having pharmacogenomics (PGx) based dosing guidelines for CYP2D6, CYP2C19, and SLCO1B1 to explore the potential of applying PGx-based decision-making into clinical practice taking drug–drug interactions (DDI) and drug–gene interactions (DGI) into account. Methods: This study is cross-sectional, using The Danish Register of Medicinal Product Statistics as the source to retrieve drug consumption data. Results: The prevalence of use in particular for antithrombotic agents (B01) and cardiovascular drugs (C) increases significantly by 4 to 6 times for diabetic users compared to the GP, whereas the increase for analgesics (N02), psycoleptics, and psychoanaleptics (N06) was somewhat less (2–3 times). The five most used PGx drugs, both in the GP and among persons with diabetes, were pantoprazole, simvastatin, atorvastatin, metoprolol, and tramadol. The prevalence of use for persons with diabetes compared to the GP (prevalence ratio) increased by an average factor of 2.9 for all PGx drugs measured. In addition, the prevalence of use of combinations of PGx drugs was 4.6 times higher for persons with diabetes compared to GP. In conclusion, the findings of this study clearly show that a large fraction of persons with diabetes are exposed to drugs or drug combinations for which there exist PGx-based dosing guidelines related to CYP2D6, CYP2C19, and SLCO1B1. This further supports the notion of accessing and accounting for not only DDI but also DGI and phenoconversion in clinical decision-making, with a particular focus on persons with diabetes. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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12 pages, 1022 KiB

Open AccessArticle

Prevalence and Determinants of Multimorbidity, Polypharmacy, and Potentially Inappropriate Medication Use in the Older Outpatients: Findings from EuroAgeism H2020 ESR7 Project in Ethiopia

by Akshaya Srikanth Bhagavathula, Mohammed Assen Seid, Aynishet Adane, Eyob Alemayehu Gebreyohannes, Jovana Brkic and Daniela Fialová

Pharmaceuticals 2021, 14(9), 844; https://doi.org/10.3390/ph14090844 - 25 Aug 2021

Cited by 12 | Viewed by 4005

Abstract

Few studies have been conducted on multimorbidity (two or more chronic diseases) and rational geriatric prescribing in Africa. This study examined the prevalence and determinants of multimorbidity, polypharmacy (five or more long-term medications), and potentially inappropriate medication (PIM) use according to the 2019 Beers criteria among the older adults attending chronic care clinics from a single institution in Ethiopia. A hospital-based cross-sectional study was conducted among 320 randomly selected older adults from 12 March 2020 to 30 August 2020. A multivariable logistic regression analysis was performed to identify the predictor variables. The prevalence of multimorbidity, polypharmacy, and PIM exposure was 59.1%, 24.1%, and 47.2%, respectively. Diuretics (10%), insulin sliding scale (8.8%), amitriptyline (7.8%), and aspirin (6.9%) were among the most frequently prescribed PIMs. Older patients experiencing pain flare-ups were more likely to have multimorbidity (adjusted odds ratio (AOR): 1.64, 95% confidence intervals: 1.13–2.39). Persistent anger (AOR: 3.33; 1.71–6.47) and use of mobility aids (AOR: 2.41, 1.35–4.28) were associated with polypharmacy. Moreover, cognitive impairment (AOR: 1.65, 1.15–2.34) and health deterioration (AOR: 1.61, 1.11–2.32) increased the likelihood of PIM exposure. High prevalence of multimorbidity and PIM use was observed in Ethiopia. Several important determinants that can be modified by applying PIM criteria in routine practice were also identified. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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15 pages, 1512 KiB

Open AccessArticle

Utility of suPAR and NGAL for AKI Risk Stratification and Early Optimization of Renal Risk Medications among Older Patients in the Emergency Department

by Anne Byriel Walls, Anne Kathrine Bengaard, Esben Iversen, Camilla Ngoc Nguyen, Thomas Kallemose, Helle Gybel Juul-Larsen, Baker Nawfal Jawad, Mads Hornum, Ove Andersen, Jesper Eugen-Olsen and Morten Baltzer Houlind

Pharmaceuticals 2021, 14(9), 843; https://doi.org/10.3390/ph14090843 - 25 Aug 2021

Cited by 14 | Viewed by 2339

Abstract

Diagnosis of acute kidney injury (AKI) based on plasma creatinine often lags behind actual changes in renal function. Here, we investigated early detection of AKI using the plasma soluble urokinase plasminogen activator receptor (suPAR) and neutrophil gelatinase-sssociated lipocalin (NGAL) and observed the impact of early detection on prescribing recommendations for renally-eliminated medications. This study is a secondary analysis of data from the DISABLMENT cohort on acutely admitted older (≥65 years) medical patients (n = 339). Presence of AKI according to kidney disease: improving global outcomes (KDIGO) criteria was identified from inclusion to 48 h after inclusion. Discriminatory power of suPAR and NGAL was determined by receiver-operating characteristic (ROC). Selected medications that are contraindicated in AKI were identified in Renbase^®. A total of 33 (9.7%) patients developed AKI. Discriminatory power for suPAR and NGAL was 0.69 and 0.78, respectively, at a cutoff of 4.26 ng/mL and 139.5 ng/mL, respectively. The interaction of suPAR and NGAL yielded a discriminatory power of 0.80, which was significantly higher than for suPAR alone (p = 0.0059). Among patients with AKI, 22 (60.6%) used at least one medication that should be avoided in AKI. Overall, suPAR and NGAL levels were independently associated with incident AKI and their combination yielded excellent discriminatory power for risk determination of AKI. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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Review

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15 pages, 429 KiB

Open AccessReview

Strategies and Tools for Supporting the Appropriateness of Drug Use in Older People

by Carlotta Lunghi, Caterina Trevisan, Michele Fusaroli, Valentina Giunchi, Emanuel Raschi, Elisa Sangiorgi, Marco Domenicali, Stefano Volpato, Fabrizio De Ponti and Elisabetta Poluzzi

Pharmaceuticals 2022, 15(8), 977; https://doi.org/10.3390/ph15080977 - 8 Aug 2022

Cited by 7 | Viewed by 2637

Abstract

Through this structured review of the published literature, we aimed to provide an up-to-date description of strategies (human-related) and tools (mainly from the digital field) facilitating the appropriateness of drug use in older adults. The evidence of each strategy and tool’s effectiveness and sustainability largely derives from local and heterogeneous experiences, with contrasting results. As a general framework, three main steps should be considered in implementing measures to improve appropriateness: prescription, acceptance by the patient, and continuous monitoring of adherence and risk-benefit profile. Each step needs efforts from specific actors (physicians, patients, caregivers, healthcare professionals) and dedicated supporting tools. Moreover, how to support the appropriateness also strictly depends on the particular setting of care (hospital, ambulatory or primary care, nursing home, long-term care) and available economic resources. Therefore, it is urgent assigning to each approach proposed in the literature the following characteristics: level of effectiveness, strength of evidence, setting of implementation, needed resources, and issues for its sustainability. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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11 pages, 823 KiB

Open AccessReview

The Potential Application of Extracellular Vesicles from Liquid Biopsies for Determination of Pharmacogene Expression

by Henok D. Habtemariam and Henk-Jan Guchelaar

Pharmaceuticals 2022, 15(2), 252; https://doi.org/10.3390/ph15020252 - 19 Feb 2022

Cited by 2 | Viewed by 2171

Abstract

Pharmacogenomics (PGx) entails the study of heritability of drug response. This may include both variability in genes related to pharmacokinetics (drug absorption, distribution, metabolism and excretion) and pharmacodynamics (e.g., drug receptors or signaling pathways). Individualizing drug therapy taking into account the genetic profile of the patient has the potential to make drug therapy safer and more effective. Currently, this approach relies on the determination of genetic variants in pharmacogenes by genotyping. However, it is widely acknowledged that large variability in gene expression is attributed to non-structural genetic variants. Therefore, at least from a theoretical viewpoint individualizing drug therapy based upon expression of pharmacogenes rather than on genotype may be advantageous but has been difficult to implement in the clinical setting. Extracellular vesicles (EVs) are lipid encapsulated structures that contain cargo such as lipids, nucleic acids and proteins. Since their cargo is tissue- and cell-specific they can be used to determine the expression of pharmacogenes in the liver. In this review, we describe methods of EV isolation and the potential of EVs isolated from liquid biopsies as a tool to determine the expression of pharmacogenes for use in personalized medicine. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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Other

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27 pages, 1276 KiB

Open AccessSystematic Review

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

by Diane Merino, Arnaud Fernandez, Alexandre O. Gérard, Nouha Ben Othman, Fanny Rocher, Florence Askenazy, Céline Verstuyft, Milou-Daniel Drici and Susanne Thümmler

Pharmaceuticals 2022, 15(6), 749; https://doi.org/10.3390/ph15060749 - 14 Jun 2022

Cited by 4 | Viewed by 3559

Abstract

Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 is pivotal in the metabolism of the APs olanzapine, clozapine, and loxapine, whose safety profile warrants caution. We aimed to shed some light on the pharmacogenetic profiles possibly associated with these drugs’ ADRs and loss of efficacy in children and youth. We conducted a systematic review relying on four databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations and checklist, with a quality assessment. Our research yielded 32 publications. The most frequent ADRs were weight gain and metabolic syndrome (18; 56.3%), followed by lack of therapeutic effect (8; 25%) and neurological ADRs (7; 21.8%). The overall mean quality score was 11.3/24 (±2.7). In 11 studies (34.3%), genotyping focused on the study of cytochromes. Findings regarding possible associations were sometimes conflicting. Nonetheless, cases of major clinical improvement were fostered by genotyping. Yet, CYP1A2 remains poorly investigated. Further studies are required to improve the assessment of the risk–benefit balance of prescription for children and youth treated with olanzapine, clozapine, and/or loxapine. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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9 pages, 289 KiB

Open AccessOpinion

Clinical Utility of Medication-Based Risk Scores to Reduce Polypharmacy and Potentially Avoidable Healthcare Utilization

by Armando Silva-Almodóvar and Milap C. Nahata

Pharmaceuticals 2022, 15(6), 681; https://doi.org/10.3390/ph15060681 - 28 May 2022

Cited by 1 | Viewed by 1695

Abstract

The management of multiple chronic health conditions often requires patients to be exposed to polypharmacy to improve their health and enhance their quality of life. However, exposure to polypharmacy has been associated with an increased risk for adverse effects, drug-drug interactions, inappropriate prescribing, medication nonadherence, increased healthcare utilization such as emergency department visits and hospitalizations, and costs. Medication-based risk scores have been utilized to identify patients who may benefit from deprescribing interventions and reduce rates of inappropriate prescribing. These risk scores may also be utilized to prompt targeted discussions between patients and providers regarding medications or medication classes contributing to an individual’s risk for harm, eventually leading to the deprescribing of the offending medication(s). This opinion will describe existing medication-based risk scores in the literature, their utility in identifying patients at risk for specific adverse events, and how they may be incorporated in healthcare settings to reduce rates of potentially inappropriate polypharmacy and avoidable healthcare utilization and costs. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives

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