Linking Pharmacogenomic Information on Drug Safety and Efficacy with Ethnic Minority Populations
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pharmaceutics Article Linking Pharmacogenomic Information on Drug Safety and Efficacy with Ethnic Minority Populations Dan Li 1, April Hui Xie 1,2, Zhichao Liu 1, Dongying Li 1, Baitang Ning 1, Shraddha Thakkar 1,3, Weida Tong 1 and Joshua Xu 1,* 1 Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA; [email protected] (D.L.); [email protected] (A.H.X.); [email protected] (Z.L.); [email protected] (D.L.); [email protected] (B.N.); [email protected] (S.T.); [email protected] (W.T.) 2 School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA 3 Office of Computational Sciences, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA * Correspondence: [email protected] Received: 8 October 2020; Accepted: 23 October 2020; Published: 25 October 2020 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. Keywords: pharmacogenomic; minority; data collection; drug; biomarker 1. Introduction Pharmacogenomic (PGx) information can be utilized to improve the medical decision-making process and avoid severe adverse drug reactions. Drug labeling with PGx information can be used to promote drug safety and drug efficacy. In general, PGx studies include evaluation of genetic or genomic variations that serve as predictive PGx biomarkers to distinguish between responders and non-responders to specific drugs [1]. Knowing whether a patient carries a specific genetic variation or has altered expression levels of genes can help prescribers to individualize drug therapy, mitigate the chance of adverse events, and optimize the effectiveness of the drug with a proper dose [2–5]. Tools such as genotyping technologies and databases have been developed to incorporate the genetic information of patients into routine clinical practice to carefully identify and prescribe a drug to the appropriate ethnic group of patients [6,7]. However, a genetic variant associated with drug responses may show a widely diverse prevalence among populations, affecting drug efficiency and drug safety for different ethnic groups. Diverse ethnicities usually harbor variability in drug Pharmaceutics 2020, 12, 1021; doi:10.3390/pharmaceutics12111021 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, 1021 2 of 10 dose requirements, and genotyping of clinically relevant PGx biomarkers has been advocated to guide drug dosing/indication optimization for different patient populations [8]. Therefore, a reliable collection of PGx information with biomarkers/drugs and their behaviors in various minority groups is needed to provide guidance for effective and safe medication to treat ethnic minority populations. Pharmaceutics 2020, 12, x FOR PEER REVIEW 2 of 10 Unfortunately, clinical studies to characterize PGx biomarkers generally have not been conducted for diverse ethnicfor different populations. ethnic groups. Although Diverse someethnicities studies usually have harbor considered variability in the drug allele dosefrequencies requirements, of genetic and genotyping of clinically relevant PGx biomarkers has been advocated to guide drug variants indosing/indication different ethnic optimization groups and for diff haveerent utilized patient populations genotype-guided [8]. Therefore, algorithms a reliable forcollection dose of selection in the prescriptionPGx information of some with drugs biomarkers/drugs such as warfarin, and their acenocoumarol, behaviors in various and minority phencopromon groups is needed to benefit to certain ethnic populationsprovide guidance [9,10], itfor remains effective challenging and safe medica to improvetion to thetreat health ethnic of minority such groups populations. with the current level of PGxUnfortunately, information. clinical Further studies systematic to characterize collection PGx biomarkers and evaluation generally have of not PGx been biomarkers conducted for and related diverse ethnic populations. Although some studies have considered the allele frequencies of genetic drugs for diversevariants in ethnic different groups ethnic isgroups needed. and have utilized genotype-guided algorithms for dose selection In thisin manuscript the prescription we of describe some drugs the such development as warfarin, and acenocoumarol, implementation and phencopromon of a bioinformatics to benefit workflow aimed tocertain enhance ethnic the populations collection [9,10], and it remains utilization challenging of PGx to improve information the health related of such groups to ethnic with minority groups (Figurethe current1). Labelinglevel of PGx of information. a number Further of drugs systematic and collection biologics and evaluation approved of PGx by biomarkers the United States and related drugs for diverse ethnic groups is needed. Food and DrugIn Administrationthis manuscript we (FDA) describe include the developm PGx informationent and implementation [11,12]; we of utilizeda bioinformatics the information in the FDAworkflow Table ofaimed Pharmacogenomic to enhance the collection Biomarkers and utilization in Drug of LabelingPGx information (TPGxBMDL) related to ethnic from the FDA website (https:minority//www.fda.gov groups (Figure/drugs 1). Labeling/science-and-research-drugs of a number of drugs and biologics/table-pharmacogenomic-biomarkers- approved by the United drug-labelingStates). Food We alsoand Drug searched Administration for PGx information(FDA) include containingPGx information relationships [11,12]; we betweenutilized the drugs and information in the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling (TPGxBMDL) from their associatedthe FDA genetic website variants(https://www.fda.gov/drugs/scienc from public resourcese-and-research-drugs/t such as DrugBankable-pharmacogenomic- [13], Pharmacogenomics Knowledgebiomarkers-drug-labeling). Base (PharmGKB) [14 We], Clinicalalso searched Interpretation for PGx information of Variants containing in Cancer relationships (CIViC) between [15], and Gene Drug Knowledgedrugs andDatabase their associated (GDKD) genetic [16 ].variants Then, from we filteredpublic resources the collected such as dataDrugBank to focus [13], on single nucleotidePharmacogenomics polymorphisms Knowledge (SNPs) in Base the (PharmGKB) reportedbiomarkers [14], Clinical Interpretation that interact of withVariants non-oncology in Cancer drugs. (CIViC) [15], and Gene Drug Knowledge Database (GDKD) [16]. Then, we filtered the collected data The alleleto frequency focus on single (AF) nucleotide information polymorphisms of SNPs (SNPs) for in di thefferent reported ethnicities biomarkers were that interact collected with from the Allele Frequencynon-oncology Aggregator drugs. The (ALFA)allele frequency project (AF) [17 information], which of provides SNPs for adifferent great ethnicities opportunity were to collect population-specificcollected from information the Allele forFrequency genetic Aggregator variants. (ALFA) In total, project allele [17], frequency which provides information a great of 67 SNPs associatedopportunity with specific to collect drug–biomarker population-specific pairs information was collected. for genetic PGxvariants. drug In total, and allele biomarker frequency pairs were information of 67 SNPs associated with specific drug–biomarker pairs was collected. PGx drug and further exploredbiomarker in pairs the PubMedwere further database, explored andin the related PubMed articles database, with and their related PubMed articles with IDs (PMIDs)their were collected.PubMed Finally, IDs all (PMIDs) data were were integratedcollected. Finally, into all a databasedata were tointegrated provide into researchers a database to with provide information regardingresearchers drugs, paired with information PGx biomarkers, regarding and drugs, associated paired PGx AFs biomarkers, of SNPs and for associated minority AFs ethnic of SNPs groups and to adjust drugfor minority doses ethnic and indications groups and to during adjust drug drug doses development and indications and during drug drug application. development and drug application. Figure 1. OverallFigure 1. data Overall collection data collection workflow. workflow. The paired The paired