Clinical Pharmacogenetics Implementation Consortium Guidelines Research Articles

Decoding pharmacogenomic test interpretation and application to patient care

AbstractPharmacogenomics is a growing area of medicine, and pharmacists across clinical practice settings have the opportunity to individualize medication selection and dosing using genetic data. However, many practicing pharmacists may feel ill‐equipped to interpret pharmacogenomic test results because of insufficient education and training. Evidence‐based, updated, and freely available resources such as the Clinical Pharmacogenetics Implementation Consortium guidelines can help pharmacists interpret and apply pharmacogenomic test results to patient care. Although gaps for the application of pharmacogenomic information exist, this commentary aims to demystify the interpretation of pharmacogenomic test results and empower pharmacists to apply genetic data alongside other clinical variables to optimize medication‐related outcomes for their patients. An “ABCD” framework is proposed to guide pharmacists through the steps: (1) Actionability—Are the gene(s) clinically relevant for the patient? (2) Be Mindful of Limitations—What are the caveats with pharmacogenomic test results and reports? (3) Clinical Practice Guidelines—How do you use pharmacogenomic test results to guide clinical decision‐making? and (4) Document and Discuss—How do you educate the patient about their pharmacogenomic test results and document the results for future use? Key concepts are illustrated using a psychiatric patient case example.

Development of a routine bedside CYP2C19 genotype assessment programfor antiplatelet therapy guidance in a community hospital catheterization laboratory.

Genotype based personalized antiplatelet therapy in the setting of percutaneous coronary intervention (PCI) has been studied in clinical trials. Despite the demonstrated risk associated with CYP2C19 loss-of-function (LoF) carriage in clopidogrel-treated PCI patients, real-world implementation of genotyping for PCI has been low. The goal of the current study was to provide CYP2C19 genotype information to the interventionalist prior to the completion of the catheterization to facilitate immediate personalized antiplatelet therapy. Routine personalization of P2Y12 inhibitor therapy for PCI in a community hospital cardiac catheterization laboratory by POC genotyping with the SpartanRx system was first offered in February 2017. A best practice advisory (BPA) based on the Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 genotype and clopidogrel therapy was placed in the electronic health record prescription medication ordering system. By December 2019, 1,052 patients had CYP2C19 genotype testing, 429 patients underwent PCI with genotype guided antiplatelet therapy, and 250 patients underwent PCI without genotype testing and received antiplatelet therapy at the discretion of the treating physician. BPA compliance was 93. 87% of LoF allele carriers were prescribed ticagrelor or prasugrel whereas 96% of non-LoF allele carriers were prescribed clopidogrel. The genotyping results were available within 1h and made immediately available for decision making by the interventional cardiologist. POC CYP2C19 genotyping is feasible in a community hospital catheterization laboratory and is associated with high rate of best practice compliance.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622.

Validating two international warfarin pharmacogenetic dosing algorithms for estimating the maintenance dose for patients in Singapore

Predicting optimal warfarin dosing is difficult due to complex pharmacodynamics and pharmacokinetics, narrow therapeutic index and susceptibility to many factors.1 Genetic variations of the CYP2C9 and VKORC1 enzymes, occurring in different frequencies in different populations, play a significant role in determining warfarin dosing.1-4 Using pharmacogenetic dosing algorithms to predict warfarin doses may shorten the time to achieve target International Normalised Ratio (INR) and stable dose.2,5 The Clinical Pharmacogenetics Implementation Consortium Guidelines 2017 Update4 recommends the Gage (WarfarinDosing.org7) and International Warfarin Pharmacogenetics Consortium (IWPC)8 pharmacogenetic algorithms.

Validating two international warfarin pharmacogenetic dosing algorithms for estimating the maintenance dose for patients in Singapore

Predicting optimal warfarin dosing is difficult due to complex pharmacodynamics and pharmacokinetics, narrow therapeutic index and susceptibility to many factors.1 Genetic variations of the CYP2C9 and VKORC1 enzymes, occurring in different frequencies in different populations, play a significant role in determining warfarin dosing.1-4 Using pharmacogenetic dosing algorithms to predict warfarin doses may shorten the time to achieve target International Normalised Ratio (INR) and stable dose.2,5 The Clinical Pharmacogenetics Implementation Consortium Guidelines 2017 Update4 recommends the Gage (WarfarinDosing.org7) and International Warfarin Pharmacogenetics Consortium (IWPC)8 pharmacogenetic algorithms.

Influence of CYP2D6 Metabolizer Status on Risperidone and Paliperidone Tolerability in Children and Adolescents.

Background: Risperidone and, to a lesser extent, paliperidone are metabolized by CYP2D6; however, there are limited data related to variation in CYP2D6 phenotypes and the tolerability of these medications in children and adolescents. Furthermore, the impact of CYP2D6 on the association of risperidone and paliperidone with hyperprolactinemia in youth is not well understood. Methods: A retrospective chart review was performed in psychiatrically hospitalized children and adolescents prescribed risperidone (n = 263, age = 3-18 years, mean age = 13 ± 3 years, 49% female) or paliperidone (n = 124, age = 5-18 years, mean age = 15 ± 2 years, 44% female) who had CYP2D6 genotyping performed as part of routine care. CYP2D6 phenotypes were determined based on Clinical Pharmacogenetics Implementation Consortium guidelines and CYP2D6 inhibitors causing phenoconversion. Adverse effects were obtained from a review of the electronic health record, and patients were selected, in part, to enrich non-normal metabolizers. Results: Among risperidone-treated patients, 45% experienced an adverse effect, whereas 36% of paliperidone-treated patients experienced adverse effects. Discontinuation of risperidone due to lack of efficacy was more frequent in the CYP2D6 normal metabolizers and ultrarapid metabolizers compared with intermediate metabolizers (IMs) and phenoconverted poor metabolizers (pPMs) (54.5% vs. 32.7%, p < 0.001). Discontinuation due to weight gain was more common among risperidone- than paliperidone-treated patients (17% vs. 7%, p = 0.011). Among those taking paliperidone, CYP2D6 was associated with discontinuation due to side effects (p = 0.008), and youth with slower CYP2D6 metabolism (i.e., pPMs and IMs) were more likely to discontinue. Hyperprolactinemia was found in 10% of paliperidone-treated patients and 5% of risperidone-treated patients, and slower CYP2D6 metabolizers required higher risperidone doses to cause hyperprolactinemia (p = 0.011). Conclusions: CYP2D6 phenotype is associated with discontinuation of risperidone due to lack of efficacy and the dose of risperidone that induced hyperprolactinemia, as well as discontinuation of paliperidone due to adverse effects. Future studies should evaluate exposure-response and toxicity relationships in risperidone- and paliperidone-treated youth.

Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes (CYP2C19 or CYP2D6), the serotonin transporter (SLC6A4), and the serotonin receptor 2A subtype (HTR2A). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC0-24; p = 0.025), trough concentrations (Ctrough; p = 0.013), and elimination half-lives (t1/2; p < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia (p = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores (p = 0.017). Escitalopram maximum concentration, AUC0-24, CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

A consideration of CYP2D6 genetic variations in the Ghanaian population as a potential 'culprit' for the tramadol 'abuse crisis'.

Cytochrome P450 2D6 is involved in the metabolism of several important medicines including opioids. Variations in CYP2D6 have been implicated in drug response and according to the Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, dosing for CYP2D6 substrates should be based on variants carried by individuals. Although CYP2D6 variations in Ghana had been previously recorded, not all variants have been reported in the Ghanaian population. In this exploratory study we set to investigate certain unreported variations in the Ghanaian population in addition to the previously reported ones and use that to understand the tramadol 'abuse' crisis that is currently being experienced in Ghana. This study employed a convenience sampling approach to include 106 unrelated participants who were recruited as part of the PHARMABIOME project. We successfully genotyped 106 samples using Iplex GOLD SNP genotyping protocol after extracting DNA from these individuals. Allele and diplotype frequencies were undertaken by counting from observed genotypes. Comparison of alleles reported from various studies were done. Unreported alleles such as *3, *9 and *41 which are classified as no function and decreased function were observed in our study cohort. In addition, variants such as (*1, *2, *4, *5, *10, *17 and *29 were observed with different frequencies. Our study showed 26% representation of intermediate metabolizers (IM) and 2% poor metabolizers (PM) in the study population. The implications for informal sector workers who use tramadol for recreational purposes, is that IMs and PMs will overdose as they may have reduced analgesic effects which will translate into increased risks of unforeseen adverse events. We therefore propose that CYP2D6 should be considered in opioid dosage while making use of these observed variations to implement new approaches to tackle the tramadol 'abuse crisis' in Ghana.

Evolution of pharmacogenomic services and implementation of a multi-state pharmacogenomics clinic across a large rural healthcare system.

Introduction: Pharmacogenomics (PGx) aims to maximize drug benefits while minimizing risk of toxicity. Although PGx has proven beneficial in many settings, clinical uptake lags. Lack of clinician confidence and limited availability of PGx testing can deter patients from completing PGx testing. A few novel PGx clinic models have been described as a way to incorporate PGx testing into the standard of care. Background: A PGx clinic was implemented to fill an identified gap in provider availability, confidence, and utilization of PGx across our health system. Through a joint pharmacist and Advanced Practice Provider (APP) collaborative clinic, patients received counseling and PGx medication recommendations both before and after PGx testing. The clinic serves patients both in-person and virtually across four states in the upper Midwest. Results: The majority of patients seen in the PGx clinic during the early months were clinician referred (77%, n = 102) with the remainder being self-referred. Patients were, on average, taking two medications with Clinical Pharmacogenetics Implementation Consortium guidelines. Visits were split almost equally between in-person and virtual visits. Conclusion: Herein, we describe the successful implementation of an interdisciplinary PGx clinic to further enhance our PGx program. Throughout the implementation of the PGx clinic we have learned valuable lessons that may be of interest to other implementors. Clinicians were actively engaged in clinic referrals and early adoption of telemedicine was key to the clinic's early successes.

Warfarin pharmacogenetics in a black Zimbabwean cohort: an observational prospective study.

Aim: A prospective observational study was conducted to evaluate the feasibility of implementing clinical guidelines for warfarin dosing in black Zimbabwean patients. Methods: CYP2C9*5, CYP2C9*6, CYP2C9*8and CYP2C9*11 and VKORC1c. 1639 G>A variations were observed in 62 study patients. Results & Conclusion: Overall, 39/62 (62.90%) participants did not receive a warfarin starting dose as would have been recommended by Clinical Pharmacogenetics Implementation Consortium guidelines. USFDA andDutch Pharmacogenetics Working Group guidelines are based on CYP2C9*2 and CYP2C9*3 only, hence, unlikely useful in this cohort, where such variants were not detected. Clinical Pharmacogenetics Implementation Consortium guidelines, on the other hand, have a specific recommendation on the African-specific variants CYP2C9*5, CYP2C9*6 and CYP2C9*11, and are hence suitable for implementation in Zimbabwe and would helpoptimize warfarin doses in patients in the study cohort.

Real-world experience of an in-house dihydropyrimidine dehydrogenase (DPYD) genotype test to guide fluoropyrimidine (FP) dosing at a multisite cancer hospital.

1534 Background: FPs, including 5-fluorouracil and capecitabine, are widely used to treat solid tumor malignancies like gastrointestinal (GI) cancers. One-third of patients (pts) develop severe toxicities which may lead to treatment delays or hospitalization. Toxicities can be partly due to genetic variations in DPYD. Herein, we describe the implementation of an in-house DPYD test and its impact on FP dosing at a multisite cancer hospital. Methods: This is an observational study of pts starting or continuing FP-based chemotherapy who received DPYD testing as part of routine care. Buccal swabs were collected in clinic and sent to an in-house lab for genotyping using a polymerase chain reaction-based Drug Metabolizing Enzyme assay that interrogates all 5 variants with moderate-to-strong evidence according to the Clinical Pharmacogenetics Implementation Consortium (CPIC) (c.1905+1G&gt;A, c.2846A&gt;T, c.1679T&gt;G, c.1236G&gt;A and c.557A&gt;G). Phenotype translations and dosing were based on CPIC guidelines. Test results and dose recommendations were uploaded to the electronic medical record (EMR) and emailed to the care team. In April 2022, pre- and post-test EMR alerts were built to prompt test ordering and dose modifications. The primary objective was to evaluate the proportion of DPYD variant carriers in tested pts receiving FP. Secondarily, we evaluated turnaround time and impact on FP dosing. Results: From March 2020-December 2022, 491 pts across 14 clinics received DPYD genotyping (54% male, 74% White, 20% Black, median age 53 years). GI cancers (~50% colorectal) represented 90% of the diagnoses. The median lab turnaround time was 3 (IQR 2-6) days. Pretreatment testing was ordered in 389 (79%) pts, of which 360 (93%) had results before cycle 1. Overall, 30 pts (6.1%) were heterozygous carriers (4.9% in pretreatment and 10.8% in reactive testing groups). Variants observed were c.1236G&gt;A (n=13), c.2846A&gt;T (n=8), c.1905+1G&gt;A (*2A) (n=4), c.557A&gt;G (n=4), and c.1679T&gt;G (*13) (n=1). FP dose was modified in 27 (90%) pts (reduced in 25, avoided in 1, discontinued in 1). Of 19 carriers with pretreatment testing, 17 (90%) received an upfront dose reduction (mean reduction 42%; 3 had subsequent dose escalations); 1 avoided FP and 1 declined chemotherapy. Of 11 carriers with reactive testing, 9 had dose reductions (mean reduction 39%) and 2 discontinued FP due to toxicity. The mean FP dose intensity at cycle 1 was 56% in pretreatment carriers, 97% in reactive carriers, and 94% in wild type pts. Conclusions: DPYD genotype-guided FP dosing is feasible at a multisite cancer hospital. In-house rapid turnaround DPYD testing identified variant carriers and resulted in treatment/dose modifications for most carriers, potentially avoiding or mitigating severe toxicities and/or hospitalization, particularly with pretreatment testing. Toxicity evaluation is ongoing.

Implementation of CYP2C19 genotyping to guide proton pump inhibitor use at an academic health center.

To describe the implementation of CYP2C19 testing into clinical practice at University of Florida (UF) Health Gainesville hospital to guide proton pump inhibitor (PPI) dosing and the lessons learned from this experience. Different CYP2C19 genotypes are associated with variability in PPI plasma concentrations and intragastric pH, which may contribute to the risk of treatment failure due to subtherapeutic concentrations and adverse effects (eg, infection, bone fracture, renal dysfunction) with sustained supratherapeutic concentrations. Based on evidence available prior to the availability of pertinent Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the UF Health Precision Medicine Program (PMP) developed clinical recommendations, provided through automated alerts at the time of a PPI order, to (1) increase the PPI dose for individuals with genotypes linked to increased CYP2C19 enzyme activity (ie, rapid and ultrarapid metabolizers) to improve the likelihood of drug effectiveness and (2) decrease the dose for individuals with decreased CYP2C19 activity (ie, intermediate and poor metabolizers) to reduce the risk of harm. The CYP2C19-PPI implementation was an iterative process that taught us key implementation lessons. Most notably, physician engagement is essential, problem lists in the medical record are unreliable, and special populations (eg, pediatric patients) need to be considered. Guiding PPI prescribing based on CYP2C19 genotype is a practical approach to potentially improve the benefit-risk ratio with PPI therapy. Physician engagement is key for successful implementation. A CPIC guideline on CYP2C19 genotype-guided PPI dosing is now available, and automated alerts may be instituted to facilitate implementation.

A retrospective analysis of preemptive pharmacogenomic testing in 22,918 individuals from China

Pharmacogenomics (PGx) examines the influence of genetic variation on drug responses. With more and more Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines published, PGx is gradually shifting from the reactive testing of single gene toward the preemptive testing of multiple genes. But the profile of PGx genes, especially for the intra-country diversity, is not well understood in China. We retrospectively collected preemptive PGx testing data of 22,918 participants from 20 provinces of China, analyzed frequencies of alleles, genotypes and phenotypes of pharmacogenes, predicted drug responses for each participant, and performed comparisons between different provinces. After analyzing 15 pharmacogenes from CPIC guidelines of 31 drugs, we found that 99.97% of individuals may have an atypical response to at least one drug; the participants carry actionable genotypes leading to atypical dosage recommendation for a median of eight drugs. Over 99% of the participants were recommended a decreased warfarin dose based on genetic factors. There were 20 drugs with high-risk ratios from 0.18% to 58.25%, in which clopidogrel showed the highest high-risk ratio. In addition, the high-risk ratio of rasburicase in GUANGDONG (risk ratio (RR)=13.17, 95%CI:4.06-33.22, p < 0.001) and GUANGXI (RR=23.44, 95%CI:8.83-52.85, p < 0.001) were significantly higher than that in all provinces. Furthermore, the diversity we observed among 20 provinces suggests that preemptive PGx testing in different geographical regions in China may need to pay more attention to specific genes. These results emphasize the importance of preemptive PGx testing and provide essential evidence for promoting clinical implementation in China.

Opportunity for pharmacogenetics testing in patients with sickle cell anemia.

<b>Background:</b> Patients with sickle cell disease (SCD) are exposed to numerous drugs over their lifespan, and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for personalized dosing. The authors' aim was to ascertain the number of drugs with CPIC guidelines prescribed to SCD patients. <b>Materials &amp; methods:</b> A search of Indiana University Health affiliated hospitals' electronic medical record identified 957 patients with a diagnosis of SCD. Drugs or drug classes with CPIC actionable guidelines ordered as inpatient and outpatient prescriptions were collected from SCD patients. <b>Results:</b> During the 16-year period, 892 (93%) patients received at least one drug that could have been dosed according to CPIC guidelines. <b>Conclusion:</b> Preemptive pharmacogenetics testing should be considered in SCD patients in order to utilize these data throughout the patient's life.

Experience, Knowledge, and Perceptions of Pharmacogenomics among Pharmacists and Nurse Practitioners in Alberta Hospitals.

Despite evidence of clinical utility and the availability of prescription guidelines, pharmacogenomics (PGx) is not broadly used in institutional settings in Canada. To inform future implementation, this study aimed to identify healthcare provider knowledge, experience, and perceptions of PGx in Alberta, Canada. An online 44-item survey was distributed to pharmacists, nurse practitioners, and physicians employed or contracted with Alberta Health Services from January to May 2022. Questions included: demographics, professional history, PGx education and exposure, knowledge, and ability to use PGx, and attitudes towards, feasibility, clinical utility, education, and implementation. Ninety-one pharmacists, 37 nurse practitioners, and 6 physicians completed the survey. Fifty-nine percent had 10 or more years of experience, and 71% practiced in urban settings. Only one-third had training in PGx, and one-quarter had used PGx. Most respondents (63%) had no knowledge of PGx resources, including the Pharmacogenomics Knowledge Base (75%), or the Clinical Pharmacogenetics Implementation Consortium guidelines (85%). While participants agreed that they understood genetic (75%) and PGx (63%) concepts, most disagreed with their ability regarding practical applications of PGx such as translating genotype to phenotype (74%) or counselling patients on results (66%). Participants agreed on the clinical utility of PGx in preventing adverse drug reactions (80%) and enhancing medication efficacy (77%), and identified oncology (62%), cardiovascular/stroke (60%), and psychiatry (56%) as therapeutic areas to consider implementation. At present, healthcare provider knowledge (87%), cost (81%), and limited guidelines/evidence (70%) are seen as the greatest barriers to implementation. Alberta healthcare providers have limited training, experience, or knowledge in PGx. However, most appear to have a positive outlook regarding clinical utility, especially within oncology, cardiology, and psychiatry. More effort is required to socialize the availability and quality of evidence and guidelines for the interpretation of PGx test results, address other knowledge gaps, and improve financial limitations.

Integrating pharmacogenomics into precision pain management.

Studies suggest wide heterogeneity in pain management response. Improved methods of pain pharmacotherapy are urgently needed to improve clinical response and safety profile of analgesics. The study or application of how genetics influence response to medications is called pharmacogenomics (PGx). PGx testing is a tool that may support more precise selection and dosing of pain medicines. PGx guidelines exist for drug-gene interactions with high levels of evidence and can be applied in clinical practice for more precise care in patients with cancer. The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a publicly funded international consortium of experts who curate published PGx data and create peer-reviewed guidelines on how to translate PGx results into actionable prescribing decisions. Given the immense need to improve pain management, it is important to increase awareness and consider application of CPIC guidelines to pain management strategies. This commentary concisely describes how PGx can be used to aid in more precise applications of pain pharmacotherapy based on the CPIC guidelines.

Correction to: Comparison of FDA Table of Pharmacogenetic Associations and Clinical Pharmacogenetics Implementation Consortium guidelines

Correction to: Comparison of FDA Table of Pharmacogenetic Associations and Clinical Pharmacogenetics Implementation Consortium guidelines

Progression of precision statin prescribing for reduction of statin-associated muscle symptoms.

Background: Statins are among the most commonly prescribed medications, and improve patient outcomes by lowering cholesterol levels, but also have side effects. Variations in statin response can be attributed to a handful of factors that include pharmacogenetics. Methods: While not a true review article, this work was written using various search engines and terms and previous and newly published Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for statins to provide a historical perspective in addition to the current status of statin-related pharmacogenetics and future perspectives. Results: This article provides historical background on statins and associated adverse effects, reviews pharmacogenetic implications, applies clinical decision support, incorporates the latest CPIC guidelinesand addresses future implications. Conclusion: Statins are a beneficial medication, but not without risk. Pharmacogenomics can help mitigate some risk factors. Clinical decision support, implementation, researchand guidelines will continue to influence statin prescribing.

Variability Between Clinical Pharmacogenetics Implementation Consortium (CPIC®) Guidelines and a Commercial Pharmacogenetics Laboratory in Genotype to Phenotype Interpretations For Patients Utilizing Psychotropics.

Clinical practice environments without in-house pharmacogenetic testing often rely on commercial laboratories, especially in the setting of pharmacogenetic testing intended to guide psychotropic use. There are occasionally differences in phenotype assignment and medication recommendations between commercial laboratories and the Clinical Pharmacogenetics Implementation Consortium (CPIC). This may be problematic as many institutions that implement pharmacogenetics consider CPIC to be an important source of guidelines for recommended prescribing actions based on genetics, as well as a tool towards standardizing pharmacogenetics implementation. Here, we completed a retrospective chart review of our academic health system’s (Michigan Medicine) electronic health record with the goal of comparing phenotypic assignment of CYP2D6 and CYP2C19 genotypes between the commercial pharmacogenetic lab used most at our institution, and CPIC. Ultimately, we identified 205 patients with available pharmacogenetic results from this lab. The prevalence of conflicting phenotype assignment was 28.8% for CYP2D6 and 32.2% for CYP2C19 genotypes when comparing the commercial lab to CPIC guidelines. In several cases, the phenotypic assignment differences for antidepressants led to significant differences in medication recommendations when comparing the commercial lab report and CPIC guidelines. These results may also have implications for medications outside of psychiatry with recommendations for dose adjustments based on CYP2D6 or CYP2C19 metabolizing phenotype.

Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers.

Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.

The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms.

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.