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Ten Years of Experience Support Pharmacogenetic Testing to Guide Individualized Drug Therapy.

ABSTRACT: Precision medicine utilizing the genetic information of genes involved in the metabolism and disposition of drugs can not only improve drug efficacy but also prevent or minimize adverse events. Polypharmacy is common among multimorbid patients and is associated with increased adverse events. One of the main objectives in health care is safe and efficacious drug therapy, which is directly correlated to the individual response to treatment. Precision medicine can increase drug safety in many scenarios, including polypharmacy. In this report, we share our experience utilizing precision medicine over the past ten years. Based on our experience using pharmacogenetic (PGx)-informed prescribing, we implemented a five-step precision medicine protocol (5SPM) that includes the assessment of the biological-clinical characteristics of the patient, current and past prescription history, and the patient's PGx test results. To illustrate our approach, we present cases highlighting the clinical relevance of precision medicine with a focus on patients with a complex history and polypharmacy.

SUBMITTER: Pena-Martin MC

PROVIDER: S-EPMC8779486 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Ten Years of Experience Support Pharmacogenetic Testing to Guide Individualized Drug Therapy.

Peña-Martín María Celsa MC García-Berrocal Belén B Sánchez-Martín Almudena A Marcos-Vadillo Elena E García-Salgado María Jesús MJ Sánchez Santiago S Lorenzo Carolina C González-Parra David D Sans Francisco F Franco Manuel M Gaedigk Andrea A Mateos-Sexmero María José MJ Sanz Catalina C Isidoro-García María M

Pharmaceutics 20220111 1

Precision medicine utilizing the genetic information of genes involved in the metabolism and disposition of drugs can not only improve drug efficacy but also prevent or minimize adverse events. Polypharmacy is common among multimorbid patients and is associated with increased adverse events. One of the main objectives in health care is safe and efficacious drug therapy, which is directly correlated to the individual response to treatment. Precision medicine can increase drug safety in many scena ...[more]

PMID: 35057056

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Project description:BackgroundIn polypharmacy patients, medication therapy management (MTM) services provide a comprehensive review of current medications and future treatment goals. Pharmacogenetics (PGx) may further optimize the identification of potential drug therapy problems (DTPs); however, the clinical utility of PGx information with a clinical decision support tool (CDST) in an MTM setting in identifying DTPs has not been systematically assessed.ObjectiveTo assess the clinical utility of an MTM service enhanced by pharmacogenetic test results and a clinical decision support tool.MethodsThis study was a post hoc analysis of the data obtained from an open-label, randomized, observational trial. Polypharmacy patients eligible for MTM service were randomly assigned to 3 intervention arms: standard MTM (SMTM), MTM incorporating CDST (CMTM), and CMTM further enhanced by PGx test results of CYP450 and VKORC1 enzymes (PGxMTM). Allocation for this post hoc analysis was based on patient adherence to the research protocol and completion of a PGx test. The number of DTPs per patient was compared across the 3 arms using analysis of variance. In addition, the frequency of serious DTPs as a categorical variable (grade 3 or above vs. lower grade) was compared across the 3 arms between PGx driven and non-PGx driven DTP recommendations. Statistical significance was tested using the chi-square test. The level of agreement between the DTP seriousness and the acceptance made by prescribers was presented as Cohen's kappa coefficient.ResultsNumbers of patients after cohort reallocation based on completion of PGx testing were 104, 180, and 58 for the SMTM, CMTM, and PGxMTM arms, respectively. On average, 3.08 DTPs were identified for each patient, which was nearly identical across all 3 arms. Blinded clinical pharmacists considered seriousness (grade 3 or 4) in 31% of the PGx-related DTPs in comparison with 4.9% of the non-PGx DTPs (P < 0.001). The more serious (i.e., grade 3 or above) DTP recommendations were more likely to be accepted by prescribers with the odds ratios of 1.95 (P = 0.05) and 2.39 (P = 0.15), when the analysis was performed for all DTPs and DTPs from the PGxMTM arm only, respectively.ConclusionsMTM enhanced by PGx testing and the clinical decision support tool did not increase the number of DTPs identified. However, PGx testing and the decision support software helps pharmacists determine more serious DTPs, and resulting subsequent recommendations were more readily accepted by a prescriber. Future study of the patient safety outcomes and overall health care costs associated with the utility of the decision support is warranted.DisclosuresNo funding was received for conducting the post hoc analysis presented in this study. Magness is employed by Magellan Health, which received funding from Genelex for costs to administrate the medication management program. The open-label randomized trial was sponsored by Genelex (Clinicaltrials.gov ID number NCT02428660). PGx tests were provided and laboratory analysis was performed by Genelex. Valerie Baron is an employee of YouScript, which created the clinical decision support tool used in this study and formerly was part of Genelex. The other authors have nothing to disclose.

Project description:Warfarin is the most widely used oral anticoagulant in clinical practice. The cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) genotypes are associated with warfarin dose requirements in China. Accurate genotyping is vital for obtaining reliable genotype-guided warfarin dosing information. The current method for individualized dosing gene polymorphism detection for warfarin has the disadvantages of being easily contaminated, time-consuming, expensive, and unsuitable for clinical use. Herein, we present a novel application, a multiplex fluorescent melting curve assay of whole-blood direct amplification of nested polymerase chain reaction (PCR), to genotyping single-nucleotide polymorphism (SNPs) rapidly that affect warfarin efficacy. This method requires only 1 µL of whole blood, no DNA extraction, takes less than 2 h, costs less than $1, and is able to accurately distinguish between different SNP sites. Polymorphic loci were detected in whole blood specimens of 181 clinical warfarin-administered patients through nested blood direct PCR fluorescence melting curve analysis and gene sequencing. The results of the nested blood direct PCR multiplex fluorescence melting curve technology were 100% consistent with those of sequencing-characterized by high accuracy and high specificity. The allele frequencies were 94.5% for A and 5.5% for C at CYP2C9*3 (rs1057910), 7.5% for G and 92.5% for A at VKORC1 (rs9923231), and 77.1% for G and 22.9% for A at CYP4F2*3 (rs2108622). For CYP2C9*2 (rs1799853), only allele C was detected, with a frequency of 100%. Warfarin doses were lower in the CYP2C9*1*1 genotype population than in the CYP2C9*1*3 population, lower in the VKORC1 (AA) population than in the VKORC1 (GG) population, and higher in individuals with the CYP4F2*3 mutation (GA/AA) compared with those with wild-type (GG). In summary, the detection and genotyping of four polymorphic SNP sites using a multiplex fluorescent melting curve assay of whole blood direct amplification through nested PCR is highly importance for guiding personalized warfarin anticoagulant therapy.

Project description:Background: Awareness about the importance of implementing DPYD pharmacogenetics in clinical practice to prevent severe side effects related to the use of fluoropyrimidines has been raised over the years. Since 2012 at the National Cancer Institute, CRO-Aviano (Italy), a diagnostic DPYD genotyping service was set up. Purpose: This study aims to describe the evolution of DPYD diagnostic activity at our center over the last 10 years as a case example of a successful introduction of pharmacogenetic testing in clinical practice. Methods: Data related to the diagnostic activity of in-and out-patients referred to our service between January 2012 and December 2022 were retrieved from the hospital database. Results: DPYD diagnostic activity at our center has greatly evolved over the years, shifting gradually from a post-toxicity to a pre-treatment approach. Development of pharmacogenetic guidelines by national and international consortia, genotyping, and IT technology evolution have impacted DPYD testing uptake in the clinics. Our participation in a large prospective implementation study (Ubiquitous Pharmacogenomics) increased health practitioners' and patients' awareness of pharmacogenetic matters and provided additional standardized infrastructures for genotyping and reporting. Nationwide test reimbursement together with recommendations by regulatory agencies in Europe and Italy in 2020 definitely changed the clinical practice guidelines of fluoropyrimidines prescription. A dramatic increase in the number of pre-treatment DPYD genotyping and in the coverage of new fluoropyrimidine prescriptions was noticed by the last year of observation (2022). Conclusion: The long path to a successful DPYD testing implementation in the clinical practice of a National Cancer Center in Italy demonstrated that the development of pharmacogenetic guidelines and genotyping infrastructure standardization as well as capillary training and education activity for all the potential stakeholders are fundamental. However, only national health politics of test reimbursement and clear recommendations by drug regulatory agencies will definitely move the field forward.

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Ten Years of Experience Support Pharmacogenetic Testing to Guide Individualized Drug Therapy.

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Ten Years of Experience Support Pharmacogenetic Testing to Guide Individualized Drug Therapy.

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