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Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 39024

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Special Issue Editors

Prof. Jacques Turgeon

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Guest Editor

College of Pharmacy, University of Florida, Lake Nona Campus, Orlando, FL, USA
Interests: drug metabolism and CYP450s; pharmacogenomics; drug-induced Long Qt Syndrome; clinical decision support systems; risk stratification and drug-related adverse events

Prof. Veronique Michaud

E-Mail Website
Guest Editor

College of Pharmacy, University of Florida, Lake Nona Campus, Orlando, FL, USA
Interests: CYP450; diabetes; drug-drug interactions; pharmacogenomics; phenoconversion; drug metabolism; drug transporters

Special Issue Information

Dear Colleagues,

Precision medicine proposes that the current knowledge and technologies be used to tailor medical decisions, treatments, practices or products to individual patients. This domain has evolved significantly from the studies of Pythagoras with fava beans 510 BC, to Snyder’s study on phenothiocarbamide in 1932, to Vogel who coined the term “pharmacogenetics” and the first textbook on pharmacogenetics by Kalow in 1962, to the first approval of a pharmacogenetic test by the FDA in 2005, and finally, to researches conducted since the Precision Medicine Initiative launched at the 2015 State of The Union address by President Obama. We propose to assemble a series of original publications on “Applied Concepts of Pharmacogenomics in Patients with Multiple Diseases and Polypharmacy”. This collection of articles should become a source of information for healthcare providers eager to apply in their clinical activities new concepts of Precision Medicine.

Best Regards,

Prof. Jacques Turgeon
Prof. Veronique Michaud
Guest Editors

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Keywords

Precision medicine
Pharmacogenomics
Phenoconversion
Opioids
Anticoagulant drugs
Antiplatelet agents
Busulfan
Drug metabolism
CYP450s
Drug transporters
Metformin
Tacrolimus
Chemotherapy
Cardiovascular drugs

Published Papers (10 papers)

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Editorial

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3 pages, 183 KiB

Open AccessEditorial

Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy

by Veronique Michaud and Jacques Turgeon

Pharmaceutics 2021, 13(2), 197; https://doi.org/10.3390/pharmaceutics13020197 - 02 Feb 2021

Cited by 3 | Viewed by 1397

Abstract

Over the last century, the process of choosing medications to treat certain diseases has evolved significantly [...] Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

Research

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17 pages, 4860 KiB

Open AccessArticle

Whole Transcription Profile of Responders to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease

by Sara Salvador-Martín, Bartosz Kaczmarczyk, Rebeca Álvarez, Víctor Manuel Navas-López, Carmen Gallego-Fernández, Ana Moreno-Álvarez, Alfonso Solar-Boga, Cesar Sánchez, Mar Tolin, Marta Velasco, Rosana Muñoz-Codoceo, Alejandro Rodriguez-Martinez, Concepción A. Vayo, Ferrán Bossacoma, Gemma Pujol-Muncunill, María J. Fobelo, Antonio Millán-Jiménez, Lorena Magallares, Eva Martínez-Ojinaga, Inés Loverdos, Francisco J. Eizaguirre, José A. Blanca-García, Susana Clemente, Ruth García-Romero, Vicente Merino-Bohórquez, Rafael González de Caldas, Enrique Vázquez, Ana Dopazo, María Sanjurjo-Sáez and Luis A. López-Fernández Show full author list Hide full author list

Pharmaceutics 2021, 13(1), 77; https://doi.org/10.3390/pharmaceutics13010077 - 08 Jan 2021

Cited by 16 | Viewed by 3057

Abstract

Background: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. Methods: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. Results: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <−0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). Conclusion: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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10 pages, 1530 KiB

Open AccessArticle

Linking Pharmacogenomic Information on Drug Safety and Efficacy with Ethnic Minority Populations

by Dan Li, April Hui Xie, Zhichao Liu, Dongying Li, Baitang Ning, Shraddha Thakkar, Weida Tong and Joshua Xu

Pharmaceutics 2020, 12(11), 1021; https://doi.org/10.3390/pharmaceutics12111021 - 25 Oct 2020

Cited by 3 | Viewed by 2382

Abstract

Numerous prescription drugs’ labeling contains pharmacogenomic (PGx) information to aid health providers and patients in the safe and effective use of drugs. However, clinical studies for such PGx biomarkers and related drug doses are generally not conducted in diverse ethnic populations. Thus, it is urgently important to incorporate PGx information with genetic characteristics of racial and ethnic minority populations and utilize it to promote minority health. In this project a bioinformatics approach was developed to enhance the collection of PGx information related to ethnic minorities to pave the way toward understanding the population-wide utility of PGx information. To address this challenge, we first gathered PGx information from drug labels. Second, we extracted data on the allele frequency information of genetic variants in ethnic minority groups from public resources. Then, we collected published research articles on PGx biomarkers and related drugs for reference. Finally, the data were integrated and formatted to build a new PGx database containing information on known drugs and biomarkers for ethnic minority groups. This database provides scientific information needed to evaluate available PGx information to enhance drug dose selection and drug safety for ethnic minority populations. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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7 pages, 550 KiB

Open AccessArticle

Frequency of CYP3A5 Genetic Polymorphisms and Tacrolimus Pharmacokinetics in Pediatric Liver Transplantation

by Jefferson Antonio Buendía, Esteban Halac, Andrea Bosaleh, María T. Garcia de Davila, Oscar Imvertasa and Guillermo Bramuglia

Pharmaceutics 2020, 12(9), 898; https://doi.org/10.3390/pharmaceutics12090898 - 22 Sep 2020

Cited by 11 | Viewed by 2141

Abstract

The evidence available in the pediatric population is limited for making clinical decisions regarding the optimization of tacrolimus (TAC) in pharmacotherapy. The objective of this study was to estimate the frequency of CYP3A5 genetic polymorphisms and their relationship with tacrolimus requirements in the pediatric population. This was a longitudinal cohort study with a two-year follow-up of 77 patients under 18 years old who underwent a liver transplant during the period 2009–2012 at the J.P. Garrahan Pediatric Hospital. Tacrolimus levels from day five up to two years after the transplant were obtained from hospital records of routine therapeutic drug monitoring. The genotyping of CYP3A5 (CYP3A5*1/*3 or *3/*3) was performed in liver biopsies from both the donor and the recipient. The frequency of CYP3A5*1 expression for recipients was 37.1% and 32.2% for donors. Patients who received an expresser organ showed lower Co/dose, especially following 90 days after the surgery. The role of each polymorphism is different according to the number of days after the transplant, and it must be taken into account to optimize the benefits of TAC therapy during the post-transplant induction and maintenance phases. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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11 pages, 1759 KiB

Open AccessArticle

Impact of GSTA1 Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation

by Veronique Michaud, My Tran, Benoit Pronovost, Philippe Bouchard, Sarah Bilodeau, Karine Alain, Barbara Vadnais, Martin Franco, François Bélanger and Jacques Turgeon

Pharmaceutics 2019, 11(9), 440; https://doi.org/10.3390/pharmaceutics11090440 - 01 Sep 2019

Cited by 15 | Viewed by 2866

Abstract

Background: Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 (GSTA1) gene variants on busulfan oral clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation. Methods: This is a quasi-experimental retrospective study in adult patients (n = 87 included in the final analyses) receiving oral busulfan. Pharmacokinetics data (area under the plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients’ files and GSTA1 *A and *B allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared. Results: Carriers of GSTA1*B exhibited lower busulfan CLo than patients with an *A/*A genotype (p < 0.002): Busulfan CLo was 166 ± 31, 187 ± 37 vs. 207 ± 47 mL/min for GSTA1*B/*B, *A/*B and *A/*A genotypes, respectively. Similar results were obtained with the tested LSMs. Using the standard AUC method, distribution of patients above the therapeutic range after the first dose was 29% for GSTA1*A/*A, 50% for *A/*B, and 65% for *B/*B. The LSMs correctly identified ≥91% of patients with an AUC above the therapeutic range. The misclassified patients had a mean difference less than 5% in their AUCs. Conclusion: Patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan oral dose. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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21 pages, 304 KiB

Open AccessCommunication

Impact of Polypharmacy on Candidate Biomarker miRNomes for the Diagnosis of Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Striking Back on Treatments

by Eloy Almenar-Pérez, Teresa Sánchez-Fito, Tamara Ovejero, Lubov Nathanson and Elisa Oltra

Pharmaceutics 2019, 11(3), 126; https://doi.org/10.3390/pharmaceutics11030126 - 18 Mar 2019

Cited by 14 | Viewed by 4207

Abstract

Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are diseases of unknown etiology presenting complex and often overlapping symptomatology. Despite promising advances on the study of miRNomes of these diseases, no validated molecular diagnostic biomarker yet exists. Since FM and ME/CFS patient treatments commonly include polypharmacy, it is of concern that biomarker miRNAs are masked by drug interactions. Aiming at discriminating between drug-effects and true disease-associated differential miRNA expression, we evaluated the potential impact of commonly prescribed drugs on disease miRNomes, as reported by the literature. By using the web search tools SM2miR, Pharmaco-miR, and repoDB, we found a list of commonly prescribed drugs that impact FM and ME/CFS miRNomes and therefore could be interfering in the process of biomarker discovery. On another end, disease-associated miRNomes may incline a patient’s response to treatment and toxicity. Here, we explored treatments for diseases in general that could be affected by FM and ME/CFS miRNomes, finding a long list of them, including treatments for lymphoma, a type of cancer affecting ME/CFS patients at a higher rate than healthy population. We conclude that FM and ME/CFS miRNomes could help refine pharmacogenomic/pharmacoepigenomic analysis to elevate future personalized medicine and precision medicine programs in the clinic. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

Review

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23 pages, 1506 KiB

Open AccessReview

Pharmacogenetic Testing: A Tool for Personalized Drug Therapy Optimization

by Kristina A. Malsagova, Tatyana V. Butkova, Arthur T. Kopylov, Alexander A. Izotov, Natalia V. Potoldykova, Dmitry V. Enikeev, Vagarshak Grigoryan, Alexander Tarasov, Alexander A. Stepanov and Anna L. Kaysheva

Pharmaceutics 2020, 12(12), 1240; https://doi.org/10.3390/pharmaceutics12121240 - 19 Dec 2020

Cited by 20 | Viewed by 8079

Abstract

Pharmacogenomics is a study of how the genome background is associated with drug resistance and how therapy strategy can be modified for a certain person to achieve benefit. The pharmacogenomics (PGx) testing becomes of great opportunity for physicians to make the proper decision regarding each non-trivial patient that does not respond to therapy. Although pharmacogenomics has become of growing interest to the healthcare market during the past five to ten years the exact mechanisms linking the genetic polymorphisms and observable responses to drug therapy are not always clear. Therefore, the success of PGx testing depends on the physician’s ability to understand the obtained results in a standardized way for each particular patient. The review aims to lead the reader through the general conception of PGx and related issues of PGx testing efficiency, personal data security, and health safety at a current clinical level. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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22 pages, 873 KiB

Open AccessReview

Can Implementation of Genetics and Pharmacogenomics Improve Treatment of Chronic Low Back Pain?

by Vladislav Suntsov, Filip Jovanovic, Emilija Knezevic, Kenneth D. Candido and Nebojsa Nick Knezevic

Pharmaceutics 2020, 12(9), 894; https://doi.org/10.3390/pharmaceutics12090894 - 21 Sep 2020

Cited by 5 | Viewed by 2893

Abstract

Etiology of back pain is multifactorial and not completely understood, and for the majority of people who suffer from chronic low back pain (cLBP), the precise cause cannot be determined. We know that back pain is somewhat heritable, chronic pain more so than acute. The aim of this review is to compile the genes identified by numerous genetic association studies of chronic pain conditions, focusing on cLBP specifically. Higher-order neurologic processes involved in pain maintenance and generation may explain genetic contributions and functional predisposition to formation of cLBP that does not involve spine pathology. Several genes have been identified in genetic association studies of cLBP and roughly, these genes could be grouped into several categories, coding for: receptors, enzymes, cytokines and related molecules, and transcription factors. Treatment of cLBP should be multimodal. In this review, we discuss how an individual’s genotype could affect their response to therapy, as well as how genetic polymorphisms in CYP450 and other enzymes are crucial for affecting the metabolic profile of drugs used for the treatment of cLBP. Implementation of gene-focused pharmacotherapy has the potential to deliver select, more efficacious drugs and avoid unnecessary, polypharmacy-related adverse events in many painful conditions, including cLBP. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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19 pages, 944 KiB

Open AccessReview

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

by Emiliene B. Tata, Melvin A. Ambele and Michael S. Pepper

Pharmaceutics 2020, 12(9), 809; https://doi.org/10.3390/pharmaceutics12090809 - 26 Aug 2020

Cited by 21 | Viewed by 3929

Abstract

Clinical research in high-income countries is increasingly demonstrating the cost- effectiveness of clinical pharmacogenetic (PGx) testing in reducing the incidence of adverse drug reactions and improving overall patient care. Medications are prescribed based on an individual’s genotype (pharmacogenes), which underlies a specific phenotypic drug response. The advent of cost-effective high-throughput genotyping techniques coupled with the existence of Clinical Pharmacogenetics Implementation Consortium (CPIC) dosing guidelines for pharmacogenetic “actionable variants” have increased the clinical applicability of PGx testing. The implementation of clinical PGx testing in sub-Saharan African (SSA) countries can significantly improve health care delivery, considering the high incidence of communicable diseases, the increasing incidence of non-communicable diseases, and the high degree of genetic diversity in these populations. However, the implementation of PGx testing has been sluggish in SSA, prompting this review, the aim of which is to document the existing barriers. These include under-resourced clinical care logistics, a paucity of pharmacogenetics clinical trials, scientific and technical barriers to genotyping pharmacogene variants, and socio-cultural as well as ethical issues regarding health-care stakeholders, among other barriers. Investing in large-scale SSA PGx research and governance, establishing biobanks/bio-databases coupled with clinical electronic health systems, and encouraging the uptake of PGx knowledge by health-care stakeholders, will ensure the successful implementation of pharmacogenetically guided treatment in SSA. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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17 pages, 568 KiB

Open AccessReview

DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report

by Theodore J. Wigle, Elena V. Tsvetkova, Stephen A. Welch and Richard B. Kim

Pharmaceutics 2019, 11(5), 199; https://doi.org/10.3390/pharmaceutics11050199 - 01 May 2019

Cited by 55 | Viewed by 6934

Abstract

5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy

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