Clinical Pharmacogenetic Research Articles

Clinical pharmacogenetic analysis in 5,001 individuals with diagnostic Exome Sequencing data

Exome sequencing is utilized in routine clinical genetic diagnosis. The technical robustness of repurposing large-scale next-generation sequencing data for pharmacogenetics has been demonstrated, supporting the implementation of preemptive pharmacogenetic strategies based on adding clinical pharmacogenetic interpretation to exomes. However, a comprehensive study analyzing all actionable pharmacogenetic alleles contained in international guidelines and applied to diagnostic exome data has not been performed. Here, we carried out a systematic analysis based on 5001 Spanish or Latin American individuals with diagnostic exome data, either Whole Exome Sequencing (80%), or the so-called Clinical Exome Sequencing (20%) (60 Mb and 17 Mb, respectively), to provide with global and gene-specific clinical pharmacogenetic utility data. 788 pharmacogenetic alleles, distributed through 19 genes included in Clinical Pharmacogenetics Implementation Consortium guidelines were analyzed. We established that Whole Exome and Clinical Exome Sequencing performed similarly, and 280 alleles in 11 genes (CACNA1S, CYP2B6, CYP2C9, CYP4F2, DPYD, G6PD, NUDT15, RYR1, SLCO1B1, TPMT, and UGT1A1) could be used to inform of pharmacogenetic phenotypes that change drug prescription. Each individual carried in average 2.2 alleles and overall 95% (n = 4646) of the cohort could be informed of at least one actionable pharmacogenetic phenotype. Differences in variant allele frequency were observed among the populations studied and the corresponding gnomAD population for 7.9% of the variants. In addition, in the 11 selected genes we uncovered 197 novel variants, among which 27 were loss-of-function. In conclusion, we provide with the landscape of actionable pharmacogenetic information contained in diagnostic exomes, that can be used preemptively in the clinics.

Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing

Purpose:The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Preemptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.Methods:In this report, we compare and contrast implementation strategies for preemptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates.Results:We found that while preemptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Lastly, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for preemptive PGx testing remain low.Conclusion:These findings should inform the establishment of future implementation efforts at institutions considering a preemptive PGx testing program.

Comparison of clinical pharmacogenetic recommendations across therapeutic areas.

Evaluations from pharmacogenetics implementation programs at major US medical centers have reported variability in the clinical adoption of pharmacogenetics across therapeutic areas. A potential cause for this variability may involve therapeutic area-specific differences in published pharmacogenetics recommendations to clinicians. To date, however, the potential for differences in clinical pharmacogenetics recommendations by therapeutic areas from prominent US guidance sources has not been assessed. Accordingly, our objective was to comprehensively compare essential elements from clinical pharmacogenetics recommendations contained within Clinical Pharmacogenetics Implementation Consortium guidelines, US Food and Drug Administration drug labels and clinical practice guidelines from US professional medical organizations across therapeutic areas. We analyzed clinical pharmacogenetics recommendation elements within Clinical Pharmacogenetics Implementation Consortium guidelines, US Food and Drug Administration drug labels and professional clinical practice guidelines through 05/24/19. We identified 606 unique clinical pharmacogenetics recommendations, with the most recommendations involving oncology (217 recommendations), hematology (79), psychiatry (65), cardiovascular (43) and anesthetic (37) medications. Within our analyses, we observed considerable variability across therapeutic areas within the following essential pharmacogenetics recommendation elements: the recommended clinical management strategy; the relevant genetic biomarkers; the organizations providing pharmacogenetics recommendations; whether routine genetic screening was recommended; and the time since recommendations were published. On the basis of our results, we infer that observed differences in clinical pharmacogenetics recommendations across therapeutic areas may result from specific factors associated with individual disease states, the associated genetic biomarkers, and the characteristics of the organizations providing recommendations.

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients

Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. Prescription of 38 level A medications based on electronic health records. Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.

Prevalence and types of inconsistencies in clinical pharmacogenetic recommendations among major U.S. sources

Clinical implementation of pharmacogenomics (PGx) is slow. Previous studies have identified some inconsistencies among clinical PGx recommendations, but the prevalence and types of inconsistencies have not been comprehensively analyzed among major PGx guidance sources in the U.S. PGx recommendations from the Clinical Pharmacogenetics Implementation Consortium, U.S. Food and Drug Administration drug labels, and major U.S. professional medical organizations were analyzed through May 24, 2019. Inconsistencies were analyzed within the following elements: recommendation category; whether routine screening was recommended; and the specific biomarkers, variants, and patient groups involved. We identified 606 total clinical PGx recommendations, which contained 267 unique drugs. Composite inconsistencies occurred in 48.1% of clinical PGx recommendations overall, and in 93.3% of recommendations from three sources. Inconsistencies occurred in the recommendation category (29.8%), the patient group (35.4%), and routine screening (15.2%). In conclusion, almost one-half of clinical PGx recommendations from prominent U.S. guidance sources contain inconsistencies, which can potentially slow clinical implementation.

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

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.

Challenges and Opportunities for Clinical Pharmacogenetic Research Studies in Resource-limited Settings: Conclusions From the Council for International Organizations of Medical Sciences–Ibero-American Network of Pharmacogenetics and Pharmacogenomics Meeting

PurposeThe symposium Health and Medicines in Indigenous Populations of America was organized by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Clinical Research in Resource-Limited Settings (RLSs) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF). It was aimed to share and evaluate investigators' experiences on challenges and opportunities on clinical research and pharmacogenetics. MethodsA total of 33 members from 22 countries participated in 2 sessions: RIBEF studies on population pharmacogenetics about the relationship between ancestry with relevant drug-related genetic polymorphisms and the relationship between genotype and phenotype in Native Americans (session 1) and case examples of clinical studies in RLSs from Asia (cancer), America (diabetes and women health), and Africa (malaria) in which the participants were asked to answer in free text their experiences on challenges and opportunities to solve the problems (session 2). Later, a discourse analysis grouping common themes by affinity was conducted. FindingsThe main result of session 1 was that the pharmacogenetics-related ancestry of the population should be considered when designing clinical studies in RLSs. In session 2, 21 challenges and 20 opportunities were identified. The social aspects represent the largest proportion of the challenges (43%) and opportunities (55%), and some of them seem to be common. ImplicationsThe main discussion points were gathered in the Declaration of Mérida/T'Hó and announced on the Parliament of Extremadura during the CIOMS-RIBEF meeting in 4 of the major Latin American autochthonous languages (Náhualth, Mayan, Miskito, and Kichwa). The declaration highlighted the following: (1) the relevance of population pharmacogenetics, (2) the sociocultural contexts (interaction with traditional medicine), and (3) the education needs of research teams for clinical research in vulnerable and autochthonous populations.

Assessment of Healthcare Professionals’ Knowledge, Attitudes, and Perceived Challenges of Clinical Pharmacogenetic Testing in Egypt

Aim: We evaluated healthcare practitioners'perspectives regarding clinical pharmacogenetics in Cairo, Egypt. Materials & methods: We administered a paper-based survey to pharmacists and physicians practicing at Children's Cancer Hospital Egypt. The survey assessed practitioners' knowledge, attitudes, and perspectives about pharmacogenetic testing. Results: The study included 184 respondents (67.9% pharmacists; 32.1% physicians. Overall, the pharmacogenetic knowledge was low (mean=41.7%) but attitudes toward pharmacogenetic testing and its potential clinical application were generally positive. Pharmacists responded more favorably than physicians to statements attributing the responsibility of applying pharmacogenetics in the clinical setting to their profession. However, several challenges were identified; the most common being: lack of pharmacogenetic knowledge and skill, lack of pharmacogenetic testing devices, and limited funding. Conclusion: Future efforts to promote pharmacogenetic implementation should focus on foundational education, practical training, and exploration of potential funding sources.

Knowledge and attitudes on pharmacogenetics among pediatricians

Increasing enthusiasm for clinical pharmacogenetic testing and the availability of pharmacogenetic-based guidelines indicate that pediatricians will increasingly be expected to interpret and apply pharmacogenetic test results into medical care. Previous studies have identified a lack of knowledge on pharmacogenetics across many physician specialties; however, this has not been systematically assessed among pediatricians. To evaluate pediatrician knowledge, attitude, and educational interest in pharmacogenetics, we surveyed physician cohorts from both the United States (U.S.) and Japan. A total of 282 pediatricians (210 from the U.S. and 72 from Japan) participated in an anonymous survey (online or hardcopy) on pharmacogenetics knowledge, perception, and education. Over 50% of all respondents had >10 years of clinical experience and >75% had some prior education in genetics. However, <10% felt they were familiar with pharmacogenetics, which was very consistent with <20% of the U.S. pediatricians correctly responding to a codeine/CYP2D6 pharmacogenetics knowledge question and <10% of U.S. pediatricians being aware of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Despite being generally unfamiliar with pharmacogenetics, >80% of all respondents indicated that implementation of clinical pharmacogenetic testing will improve efficacy and safety, and that pediatricians should be capable of applying this testing to their practice. Moreover, the majority (83.1%) were interested in educational opportunities on pharmacogenetics, particularly on result interpretation and therapeutic recommendations. Taken together, these data indicate that although practical knowledge of pharmacogenetics among pediatricians in the U.S. and Japan is currently very low, their interest in clinical pharmacogenetics and related education is high, which will likely facilitate future implementation.

Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry.

Efavirenz (more specifically the S-enantiomer) is a cornerstone antiretroviral therapy for treatment of HIV infection. The major primary metabolite is S-8-hydroxyefavirenz, which does not have antiretroviral activity but is neurotoxic. Cytochrome P450 2B6 (CYP2B6) is the major enzyme catalyzing S-8-hydroxyefavirenz formation. CYP2B6 genetics and drug interactions are major determinants of clinical efavirenz disposition and dose adjustment. In addition, as a prototypic CYP2B6 substrate, S-efavirenz and analogs can inform on the structure, activity, catalytic mechanisms, and stereoselectivity of CYP2B6. Metabolism of R-efavirenz by CYP2B6 remains unexplored. This investigation assessed S-efavirenz metabolism by clinically relevant CYP2B6 genetic variants. This investigation also evaluated R-efavirenz hydroxylation by wild-type CYP2B6.1 and CYP2B6 variants. S-Efavirenz 8-hydroxylation by wild-type CYP2B6.1 and variants exhibited positive cooperativity and apparent cooperative substrate inhibition. On the basis of Clmax values, relative activities for S-efavirenz 8-hydroxylation were in the order CYP2B6.4 > CYP2B6.1 ≈ CYP2B6.5 ≈ CYP2B6.17 > CYP2B6.6 ≈ CYP2B6.7 ≈ CYP2B6.9 ≈ CYP2B6.19 ≈ CYP2B6.26; CYP2B6.16 and CYP2B6.18 showed minimal activity. Rates of R-efavirenz metabolism were approximately 1/10 those of S-efavirenz for wild-type CYP2B6.1 and variants. On the basis of Clmax values, there was 14-fold enantioselectivity (S > R-efavirenz) for wild-type CYP2B6.1, and 5- to 22-fold differences for other CYP2B6 variants. These results show that both CYP2B6 516G > T (CYP2B6*6 and CYP2B6*9) and 983T > C (CYP2B6*16 and CYP2B6*18) polymorphisms cause canonical diminishment or loss-of-function variants for S-efavirenz 8-hydroxylation, provide a mechanistic basis for known clinical pharmacogenetic differences in efavirenz disposition, and may predict additional clinically important variant alleles. Efavirenz is the most stereoselective CYP2B6 drug substrate yet identified and may be a useful probe for the CYP2B6 active site and catalytic mechanisms. SIGNIFICANCE STATEMENT: Clinical disposition of the antiretroviral S-efavirenz is affected by CYP2B6 polymorphisms. Expressed CYP2B6 with 516G>T (CYP2B6*6 and CYP2B6*9), and 983T>C (CYP2B6*16 and CYP2B6*18) polymorphisms had a diminishment or loss of function for efavirenz 8-hydroxylation. This provides a mechanistic basis for efavirenz clinical pharmacogenetics and may predict additional clinically important variant alleles. Efavirenz metabolism showed both cooperativity and cooperative substrate inhibition. With greater than 10-fold enantioselectivity (S- vs. R- metabolism), efavirenz is the most stereoselective CYP2B6 drug substrate yet identified. These findings may provide mechanistic insights.

The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems.

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC)

Introduction:Reporting and sharing pharmacogenetic test results across clinical laboratories and electronic health records is a crucial step toward the implementation of clinical pharmacogenetics, but allele function and phenotype terms are not standardized. Our goal was to develop terms that can be broadly applied to characterize pharmacogenetic allele function and inferred phenotypes.Materials and methods:Terms currently used by genetic testing laboratories and in the literature were identified. The Clinical Pharmacogenetics Implementation Consortium (CPIC) used the Delphi method to obtain a consensus and agree on uniform terms among pharmacogenetic experts.Results:Experts with diverse involvement in at least one area of pharmacogenetics (clinicians, researchers, genetic testing laboratorians, pharmacogenetics implementers, and clinical informaticians; n = 58) participated. After completion of five surveys, a consensus (>70%) was reached with 90% of experts agreeing to the final sets of pharmacogenetic terms.Discussion:The proposed standardized pharmacogenetic terms will improve the understanding and interpretation of pharmacogenetic tests and reduce confusion by maintaining consistent nomenclature. These standard terms can also facilitate pharmacogenetic data sharing across diverse electronic health care record systems with clinical decision support.Genet Med19 2, 215–223.

Personalizing medicine with clinical pharmacogenetics

Clinical genetic testing has grown substantially over the past 30 years as the causative mutations for Mendelian diseases have been identified, particularly aided in part by the recent advances in molecular-based technologies. Importantly, the adoption of new tests and testing strategies (e.g., diagnostic confirmation, prenatal testing, and population-based carrier screening) has often been met with caution and careful consideration before clinical implementation, which facilitates the appropriate use of new genetic tests. Although the field of pharmacogenetics was established in the 1950s, clinical testing for constitutional pharmacogenetic variants implicated in interindividual drug response variability has only recently become available to help clinicians guide pharmacotherapy, in part due to US Food and Drug Administration-mediated product insert revisions that include pharmacogenetic information for selected drugs. However, despite pharmacogenetic associations with adverse outcomes, physician uptake of clinical pharmacogenetic testing has been slow. Compared with testing for Mendelian diseases, pharmacogenetic testing for certain indications can have a lower positive predictive value, which is one reason for underutilization. A number of other barriers remain with implementing clinical pharmacogenetics, including clinical utility, professional education, and regulatory and reimbursement issues, among others. This review presents some of the current opportunities and challenges with implementing clinical pharmacogenetic testing.

Development and implementation of a pharmacist-managed clinical pharmacogenetics service

The development and implementation of a pharmacist-managed clinical pharmacogenetics service are described. A pharmacist-managed clinical pharmacogenetics service was designed and implemented at an academic specialty hospital to provide clinical pharmacogenetic testing for gene products important to the pharmacodynamics of medications used in the hospital's patients. A series of accredited educational seminars were conducted for our pharmacists to establish competencies in providing pharmacogenetic consults for the genes to be tested by the clinical pharmacogenetics service. The service was modeled after and integrated with an already-established clinical pharmacokinetics service. A steering committee was formed to evaluate the use of available tests, new evidence for implementation of additional tests, and other service quality metrics. All clinical pharmacogenetic test results are first reported to one of the pharmacists, who reviews the result and provides a written consultation. The consultation includes an interpretation of the result and recommendations for any indicated changes to therapy. In 2009, 136 clinical pharmacogenetic tests were performed. The service has been met with positive clinician feedback. The successful implementation of this service highlights the leadership role that pharmacists can take in moving pharmacogenetics from research to patient care. The development of and experience with a pharmacist-managed clinical pharmacogenetics service are described. The program's success has depended on collaboration between the clinical laboratory and pharmacists, and pharmacists' pharmacogenetic recommendations have been well accepted by prescribers.

Extreme discordant phenotype methodology: an intuitive approach to clinical pharmacogenetics

Pharmacogenetics represents “the study of variability in drug response due to heredity”. Of the more than six dozen pharmacogenetic differences described in the medical literature, the majority of these variations occurs in drug-metabolizing enzyme genes and others in drug receptor and drug transporter genes, whereas many others have not yet been explained on a molecular basis. It is clear that “drug efficacy” or “drug toxicity” represents a multiplex phenotype, i.e. interaction between the drug (or its metabolites) and the gene products (enzymes, receptors, other targets) of two, and usually many more than two, genes. Because there is a gradient in these phenotypes (efficacy or toxicity), it is extremely important to select patients having the most unequivocal phenotype possible—if one wishes to find the gene(s) responsible for the trait. The method of “extreme discordant phenotype” (EDP) is therefore highly recommended. Using EDP methodology, DNA sequence variants (genotype) can be unconditionally correlated with drug efficacy or toxicity (phenotype). EDP methodology is mathematically intuitive and, in essence, has been used in a number of previous clinical pharmacogenetic studies. This EDP approach should be applicable to virtually any pharmaceutical agent in patient populations.