Clinical Pharmacogenetics Implementation Consortium 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.

Case report on Pharmacogenetic guided warfarin dosing in a postoperative valve replacement patient

Patient underwent mitral valve replacement with mechanical valve and was initiated on oral anticoagulation with standard dose of warfarin. She developed supra therapeutic INR levels. Genotyping of CYP2C9 and VKORC1 encoding genes revealed homozygous variation of CYP2C9*3*3 and heterozygous variation of VKORC1 G>A making her hypersensitive to warfarin. Based on this study result and Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline, a low dose of warfarin (0.5mg per day) was prescribed, to achieve a therapeutic INR of 2.5 to 3.5 and adverse drug effects were avoided.

Recommendations for pharmacogenetic testing in clinical practice guidelines in the US.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US. Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization. A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing.

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.

Precision dosing for patients on tricyclic antidepressants.

We aim to develop a personalized dosing tool for tricyclic antidepressants (TCAs) that integrates CYP2D6 and CYP2C19 gene variants and their effects while also considering the polypharmacy effect. The study first adopted a scoring system that assigns weights to each genetic variant. A formula was then developed to compute the effect of both genes' variants on drug dosing. The output of the formula was assessed by a comparison with the clinical pharmacogenetics implementation consortium recommendation. The study also accounts for the effect of the co-administration of inhibitors and inducers on drug metabolism. Accordingly, a user-friendly tool, Clinical Dosing Tool ver.2, was created to assist clinicians in dosing patients on TCAs. The study provides a comprehensive list of all alleles with corresponding activity values and phenotypes for both enzymes. The tool calculated an updated area under the curve ratio that utilizes the effects of both enzymes' variants for dose adjustment. The tool provided a more accurate individualized dosing that also integrates the polypharmacy effect. To the best of our knowledge, the literature misses such a tool that provides a numerical adjusted dose based on continuous numerical activity scores for the considered patients' alleles and phenoconversion.

Empowering personalized pharmacogenomics with generative AI solutions.

This study evaluates an AI assistant developed using OpenAI's GPT-4 for interpreting pharmacogenomic (PGx) testing results, aiming to improve decision-making and knowledge sharing in clinical genetics and to enhance patient care with equitable access. The AI assistant employs retrieval-augmented generation (RAG), which combines retrieval and generative techniques, by harnessing a knowledge base (KB) that comprises data from the Clinical Pharmacogenetics Implementation Consortium (CPIC). It uses context-aware GPT-4 to generate tailored responses to user queries from this KB, further refined through prompt engineering and guardrails. Evaluated against a specialized PGx question catalog, the AI assistant showed high efficacy in addressing user queries. Compared with OpenAI's ChatGPT 3.5, it demonstrated better performance, especially in provider-specific queries requiring specialized data and citations. Key areas for improvement include enhancing accuracy, relevancy, and representative language in responses. The integration of context-aware GPT-4 with RAG significantly enhanced the AI assistant's utility. RAG's ability to incorporate domain-specific CPIC data, including recent literature, proved beneficial. Challenges persist, such as the need for specialized genetic/PGx models to improve accuracy and relevancy and addressing ethical, regulatory, and safety concerns. This study underscores generative AI's potential for transforming healthcare provider support and patient accessibility to complex pharmacogenomic information. While careful implementation of large language models like GPT-4 is necessary, it is clear that they can substantially improve understanding of pharmacogenomic data. With further development, these tools could augment healthcare expertise, provider productivity, and the delivery of equitable, patient-centered healthcare services.

Knowledgeand perceptions of pharmacogenomics among pharmacists in Manitoba, Canada.

Objective: This work was designed to describe the knowledge and perceptions of pharmacogenomics (PGx) among pharmacists in the Canadian province of Manitoba. Methods: A 40-item, web-based survey was distributed to pharmacists in Manitoba. Results: Of 74 participants, one third had some education or training in PGx, and 12.2% had used PGx test results in their practice. Participants' self-rated knowledge of PGx testing and common PGx resources (e.g., Pharmacogenomics Knowledge Base, Clinical Pharmacogenetics Implementation Consortium) was low. Most pharmacists surveyed believe that PGx can improve medication efficacy (82.4%) or prevent adverse drug reactions (81.1%). Most (91%) desired more education on PGx. Conclusion: Manitoba pharmacists reported positive perceptions toward PGx. However, they are currently underprepared to implement PGx into practice.

ADME Gene-Related Pharmacogenomic Labeling of FDA-Approved Drugs: Comparison with Clinical Pharmacogenetics Implementation Consortium (CPIC) Evidence Levels.

Pharmacogenomics (PGx) can facilitate the transition to patient-specific drug regimens and thus improve their efficacy and reduce toxicity. The aim of this study was to evaluate the overlap of PGx classification for drug absorption, distribution, metabolism, and elimination (ADME)-related genes in the U.S. Food and Drug Administration (FDA) PGx labeling and in the Clinical Pharmacogenetics Implementation Consortium (CPIC) database. FDA-approved drugs and PGx labeling for ADME genes were identified in the CPIC database. Drugs were filtered by their association with ADME (pharmacokinetics)-related genes, PGx FDA labeling class, and CPIC evidence level. FDA PGx labeling was classified as either actionable, informative, testing recommended, or testing required, and varying CPIC evidence levels as either A, B, C, or D. From a total of 442 ADME and non-ADME gene-drug pairs in the CPIC database, 273, 55, and 48 pairs were excluded for lack of FDA labeling, mixed CPIC evidence level provisional classification, and non-ADME gene-drug pairs, respectively. The 66 ADME gene-drug pairs were classified into the following categories: 10 (15%) informative, 49 (74%) actionable, 6 (9%) testing recommended, and 1 (2%) testing required. CYP2D6 was the most prevalent gene among the FDA PGx labeling. From the ADME gene-drug pairs with both FDA and CPIC PGx classification, the majority of the drugs were for depression, cancer, and pain medications. The ADME gene-drug pairs with FDA PGx labeling considerably overlap with CPIC classification; however, a large number of ADME gene-drug pairs have only CPIC evidence levels but not FDA classification. PGx actionable labeling was the most common classification, with CYP2D6 as the most prevalent ADME gene in the FDA PGx labeling. Health professionals can impact therapeutic outcomes via pharmacogenetic interventions by analyzing and reconciling the FDA labels and CPIC database.

Opportunities for Pharmacogenetic Testing to Guide Dosing of Medications in Youths With Medicaid

There are an increasing number of medications with a high level of evidence for pharmacogenetic-guided dosing (PGx drugs). Knowledge of the prevalence of dispensings of PGx drugs and their associated genes may allow hospitals and clinical laboratories to determine which pharmacogenetic tests to implement. To investigate the prevalence of outpatient dispensings of PGx drugs among Medicaid-insured youths, determine genes most frequently associated with PGx drug dispenses, and describe characteristics of youths who were dispensed at least 1 PGx drug. This serial cross-sectional study includes data from 2011 to 2019 among youths aged 0 to 17 years in the Marketscan Medicaid database. Data were analyzed from August to December 2022. PGx drugs were defined as any medication with level A evidence as determined by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The number of unique youths dispensed each PGx drug in each year was determined. PGx drugs were grouped by their associated genes for which there was CPIC level A evidence to guide dosing, and a dispensing rate (No. of PGx drugs/100 000 youths) was determined for each group for the year 2019. Demographics were compared between youths dispensed at least 1 PGx drug and those not dispensed any PGx drugs. The number of Medicaid-insured youths queried ranged by year from 2 078 683 youths in 2011 to 4 641 494 youths in 2017, including 4 126 349 youths (median [IQR] age, 9 [5-13] years; 2 129 926 males [51.6%]) in 2019. The proportion of Medicaid-insured youths dispensed PGx drugs increased from 289 709 youths (13.9%; 95% CI, 13.8%-14.0%) in 2011 to 740 072 youths (17.9%; 95% CI, 17.9%-18.0%) in 2019. Genes associated with the most frequently dispensed medications were CYP2C9, CYP2D6, and CYP2C19 (9197.0 drugs [95% CI, 9167.7-9226.3 drugs], 8731.5 drugs [95% CI, 8702.5-8759.5 drugs], and 3426.8 drugs [95% CI, 3408.1-3443.9 drugs] per 100 000 youths, respectively). There was a higher percentage of youths with at least 1 chronic medical condition among youths dispensed at least 1 PGx drug (510 445 youths [69.0%; 95% CI, 68.8%-69.1%]) than among 3 386 277 youths dispensed no PGx drug (1 381 544 youths [40.8%; 95% CI, 40.7%-40.9%) (P < .001) in 2019. In this study, there was an increasing prevalence of dispensings for PGx drugs. This finding suggests that pharmacogenetic testing of specific drug-gene pairs should be considered for frequently prescribed PGx drugs and their implicated genes.

NUDT15 and TPMT polymorphisms in three distinct native populations of the Brazilian Amazon.

This is the first report of the distribution of TPMT and NUDT15 single nucleotide polymorphisms and metabolic phenotypes associated with cytotoxicity of thiopurine drugs, in indigenous groups of Brazilian Amazon: Munduruku, Paiter-Suruí and Yanomami. The minor allele frequency (MAF) of NUDT15 rs116855232 did not differ significantly across the groups; TPMT rs1800462 was absent, while rs1800460 and rs1142345 were in strong linkage disequilibrium, and 10- and 30-fold more common in Paiter-Suruí. Indeed, the MAFs in Paiter-Surui (0.193 and 0.188) are the largest report globally. The distribution of combined NUDT15/TPMT metabolic phenotypes differed significantly (p < 0.0001) and largely (Cramér´s V = 0.37) across cohorts. This has important pharmacogenetic implications: the Clinical Pharmacogenetics Implementation Consortium recommendations to reduce or consider reduction of thiopurine dose applies to 4.4% Yanomami, 5.6% Munduruku, versus 41% Paiter-Suruí. The proportion of Paiter-Suruí at risk of thiopurine intolerance is 3- to 4-fold higher than any other population worldwide.

Pharmacogenetics in Child and Adolescent Psychiatry: Background and Evidence-Based Clinical Applications.

The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic factors. Pharmacogenetics (PGx) in child and adolescent psychiatry can potentially improve treatment outcomes and minimize adverse drug reactions. This article reviews key pharmacokinetic and pharmacodynamic genes and principles of pharmacogenetic testing and discusses the evidence base for clinical decision-making concerning PGx testing. This article reviews current guidelines from the United States Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Dutch Pharmacogenetics Working Group (DPWG) and explores potential future directions. This review discusses key clinical considerations for clinicians prescribing psychotropic medications in children and adolescents, focusing on antidepressants, antipsychotics, stimulants, norepinephrine reuptake inhibitors, and alpha-2 agonists. Finally, this review synthesizes the practical use of pharmacogenetic testing and clinical decision support systems.

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.

Implementation of clopidogrel pharmacogenetic clinical decision support for a preemptive return of results program.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. To describe our experiences implementing and iterating CYP2C19 genotype-guided clopidogrel pharmacogenetic clinical decision support (CDS) tools over time in the setting of a large health system-wide, preemptive pharmacogenomics program. Clopidogrel-treated patients who are genetically predicted cytochrome P450 isozyme 2C19 intermediate or poor metabolizers have an increased risk of atherothrombotic events, some of which can be life-threatening. The Clinical Pharmacogenetics Implementation Consortium provides guidance for the use of clopidogrel based on CYP2C19 genotype in patients with cardiovascular and cerebrovascular diseases. Our multidisciplinary team implemented an automated, interruptive alert that fires when clopidogrel is ordered or refilled for biobank participants with structured CYP2C19 intermediate or poor metabolizer genomic indicators in the electronic health record. The implementation began with a narrow cardiovascular indication and setting and was then scaled in 4 primary dimensions: (1) clinical indication; (2) availability across health-system locations; (3) care venue (e.g., inpatient vs outpatient); and (4) provider groups (eg, cardiology and neurology). We iterated our approach over time based on evolving clinical evidence and proactive strategies to optimize CDS maintenance and sustainability. A key facilitator of expansion was socialization of the broader pharmacogenomics initiative among our academic medical center community, accompanied by clinician acceptance of pharmacogenetic alerts in practice. A multidisciplinary collaboration is recommended to facilitate the use of CYP2C19 genotype-guided antiplatelet therapy in patients with cardiovascular and cerebrovascular diseases. Evolving clopidogrel pharmacogenetic evidence necessitates thoughtful iteration of implementation efforts and strategies to optimize long-term maintenance and sustainability.

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.

Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.

Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-). Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP. We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

Common dihydropyrimidinase ( DPYS ) genetic variations do not predict fluoropyrimidine-related chemotherapy toxicity in a Canadian cohort.

Known genetic variations in dihydropyrimidine dehydrogenase (gene name DPYD ) do not fully predict patients at risk for severe fluoropyrimidine-associated chemotherapy toxicity. Dihydropyrimidinase (gene name DPYS ), the second catabolic enzyme in fluoropyrimidine metabolism, has been noted as a potential determinant of variation in fluoropyrimidine metabolism and response. In this study, we genotyped for DPYS c.-1T>C (rs2959023), c.265-58T>C (rs2669429) and c.541C>T (rs36027551) in a Canadian cohort of 248 patients who were wild type for Clinical Pharmacogenetics Implementation Consortium recommended DPYD variants and had received a standard dose of fluoropyrimidine chemotherapy. None of our patients were found to carry the DPYS c.541C>T variant, while the minor allele frequencies were 63% and 54% for c.-1T>C and c.265-58T>C, respectively. There was no association between DPYS c.-1T>C wild type and heterozygote [odds ratio (OR) (95% confidence interval, CI) = 1.10 (0.51-2.40)] or homozygote variant carriers [OR (95% CI) = 1.22 (0.55-2.70)], or between DPYS c.265-58T>C wild-type patients and heterozygote [OR (95% CI) = 0.93 (0.48-1.80)] or homozygote variant carriers [OR (95% CI) = 0.76 (0.37-1.55)] in terms of fluoropyrimidine-associated toxicity. Therefore, in our cohort of mostly Caucasian Canadians, genetic variations in DPYS do not appear to be a significant contributor to severe fluoropyrimidine-associated toxicity.

Caffeine, Lorazepam, and Morphine Use in Neonatal Intensive Care Unit Population and Potential Relevance of Pharmacogenomics

Abstract Medications are critical for managing acutely ill infants in neonatal intensive care unit (NICU). Tailoring therapies to individual differences in response and dose requirements might help improve outcomes. However, tools for optimizing pharmacotherapy remain limited. In this retrospective study, we explored the potential utility of pharmacogenetics for commonly prescribed NICU medications. All patients admitted to our local NICU March-December, 2022 were eligible for inclusion in the study. In infants who received at least three doses of one or more medications, we extracted DNA from residual EDTA blood collected for routine clinical care according to IRB-approved study protocols. Demographic, pharmacy, and clinical information was recorded retrospectively. Targeted pharmacogenetics testing was performed with a custom TaqMan OpenArray and a QuantStudio 12K Flex (ThermoFisher Scientific) with DNA normalized to 50 ng/mL. Results were analyzed using Genotyper Software version 1.3 and allele calls were made based on the combination of variants detected and consensus nomenclature. For drugs administered to at least 30 NICU patients, pharmacogenes were evaluated for variant allele frequency and potential clinical relevance. Of the 132 patients enrolled, 81 were male. Average length of stay was 47 days. Of the 64 different medications prescribed to at least one infant, for 15 of them are described clinical annotations with specific pharmacogenes by the PharmGKB and/or Clinical Pharmacogenetics Implementation Consortium. Of those 15 medications, three were administered at least three times to at least 30 infants: caffeine (n=102), morphine (n=56), and lorazepam (n=31). The associated pharmacogenes were CYP1A2 (caffeine); CYP3A4, OPRM1, COMT, ABCB1 (morphine); and UGT2B15 (lorazepam). Relevant to the rate of clearance of caffeine, rs2069514 (CYP1A2) was heterozygous in 18% of patients, and homozygous in 5%. Relevant to the rate of clearance of morphine, CYP3A4*22 was heterozygous in 5%. The common variants associated with response to morphine, c.472G&amp;gt;A (COMT) and c.118A&amp;gt;G (OPRM1) were heterozygous in 43% and 26%, and were homozygous in 22% and 8%, respectively. The transporter variant ABCB1*2 was heterozygous in 6% and homozygous in 11%. Relevant to the rate of clearance of lorazepam, UGT2B15*2 (rs1902023) was heterozygous in 45%, and homozygous in 31%. Correlation of pharmacogenetic results to specific clinical phenotypes is currently in progress. Pharmacogenetic variants relevant to commonly prescribed medications in the NICU are prevalent. Further clinical correlation of pharmacogenetic results may help inform selection and dosing of medications for critically ill NICU infants. This research may also facilitate detection and definition of new drug-gene associations unique to this patient population.