Association of genetic variants in CYP3A5, DRD2 and NK1R with opioid overdose.

In 2023, 3651 Ohioans died because of an opioid overdose. Of those opioid overdoses, 3579 (98%) of which were attributed to fentanyl. We evaluated the association between 180 candidate single nucleotide polymorphisms (SNPs) and self-reported, nonfatal opioid overdose history from a prospective sample of 1301 adult patients (≥18 years of age) seen in three urban emergency departments in Ohio. Candidate SNPs included 120 related to the dopamine reward pathway and 60 related to pharmacokinetics. Of the 821 patients who reported having been exposed to opioids in their lifetime, 95 (11.6%) also reported having experienced an opioid-related overdose. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and opioid overdose, correcting for multiple comparisons. Three SNPs, located in three different genes were associated with opioid overdose: increased odds with CYP3A5 (rs776746) and DRD2 (rs4436578), and decreased odds with NKIR (rs6715729). Homozygotic CYP3A5 (rs776746) had the highest adjusted odds ratio (OR) of 6.96 (95% CI [2.45, 29.23]) and homozygotic NK1R (rs6715729) had the lowest OR of 0.28 (95% CI [0.14, 0.54). Given that CYP3A5 (rs776746) has been associated with increased plasma concentrations of fentanyl, rs776746 could potentially be utilized as a prognostic risk indicator for the potential of an opioid overdose. NK1R regulates the expression of the neurokinin-1 receptor, a regulator of respiration and NK1R (rs6715729) represents a novel genetic marker for a decreased risk of opioid overdose risk.

Opioid use disorder risk alleles in self-reported assigned African American/Afro-Caribbean and European biogeographical genetic ancestry groups and in males and females.

The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the African/Afro-Caribbean BGAG had slightly lower predicted probabilities of OUD. Variant carriers in the European BGAG had slightly higher predicted probabilities of OUD. Relative to sex, all the six variants met evaluation criteria (five subjects for all sex, variant, and OUD status combinations). No statistically significant interactions were found between a given variant, BGAGs and sex. Findings suggest variant testing relative to OUD risk can be applied across BGAGs and sex, however, studies in larger populations are needed.

Screening for problematic opioid use in the emergency department: Comparison of two screening measures.

Study objective: Earlier intervention for opioid use disorder (OUD) may reduce long-term health implications. Emergency departments (EDs) in the United States treat millions with OUD annually who may not seek care elsewhere. Our objectives were (1) to compare two screening measures for OUD characterization in the ED and (2) to determine the proportion of ED patients screening positive for OUD and those who endorse other substance use to guide future screening programs. Methods: A cross-sectional study of randomly selected adult patients presenting to three Midwestern US EDs were enrolled, with duplicate patients excluded. Surveys were administered via research assistant and documented on tablet devices. Demographics were self-reported, and OUD positivity was assessed by the DSM 5 checklist and the WHO ASSIST 3.1. The primary outcome was the concordance between two screening measures for OUD. Our secondary outcome was the proportion of ED patients meeting OUD criteria and endorsed co-occurring substance use disorder (SUD) criteria. Results: We enrolled 1305 participants; median age of participants was 46 years (range 18-84), with 639 (49.0%) Non-Hispanic, White, and 693 (53.1%) female. Current OUD positivity was identified in 17% (222 out of 1305) of the participants via either DSM-5 (two or more criteria) or ASSIST (score of 4 or greater). We found moderate agreement between the measures (kappa = 0.56; Phi coefficient = 0.57). Of individuals screening positive for OUD, 182 (82%) endorsed criteria for co-occurring SUD. Conclusions: OUD is remarkably prevalent in ED populations, with one in six ED patients screening positive. We found a high prevalence of persons identified with OUD and co-occurring SUD, with moderate agreement between measures. Developing and implementing clinically feasible OUD screening in the ED is essential to enable intervention.

Advancing Pharmacogenomics-Based Care Through Interprofessional Education.

As genomic medicine becomes increasingly complex, pharmacists need to work collaboratively with other healthcare professionals to provide genomics-based care. The core pharmacist competencies in genomics were recently updated and mapped to the entrustable professional activities (EPAs). The new competency that is mapped to the "Interprofessional Team Member" EPA domain emphasizes the role of pharmacists as the pharmacogenomics experts in an interprofessional healthcare team. Interprofessional education (IPE) activities involving student pharmacists and students from other healthcare disciplines are crucial to prepare student pharmacists for a team-based approach to patient-centered care. This commentary discusses the pharmacogenomics-focused IPE activities implemented by 3 programs, the challenges faced, and the lessons learned. It also discusses strategies to develop pharmacogenomics-focused IPE activities based on existing resources. Developing pharmacogenomics-focused IPE activities will help prepare pharmacy graduates with the knowledge, skills, and attitudes to lead collaborative, interprofessional teams in the provision of pharmacogenomics-based care, consistent with the standards described in the genomics competencies for pharmacists.

Designer benzodiazepine rat pharmacokinetics: A comparison of alprazolam, flualprazolam and flubromazolam.

Designer benzodiazepines, including flualprazolam and flubromazolam, are clandestinely produced to circumvent federal regulations. Although flualprazolam and flubromazolam are structurally similar to alprazolam, they do not have an approved medical indication. Flualprazolam differs from alprazolam by the addition of a single fluorine atom. Whereas, flubromazolam differs by the addition of a single fluorine atom and substitution of a bromine for a chlorine atom. The pharmacokinetics of these designer compounds have not been extensively evaluated. In the present study, we evaluated flualprazolam and flubromazolam in a rat model and compared the pharmacokinetics of both compounds to alprazolam. Twelve male, Sprague-Dawley rats were given a 2 mg/kg subcutaneous dose of alprazolam, flualprazolam and flubromazolam and plasma pharmacokinetic parameters were evaluated. Both compounds displayed significant two-fold increases in volume of distribution and clearance. Additionally, flualprazolam displayed a significant increase in half-life leading to a nearly double half-life when compared to alprazolam. The findings of this study demonstrate that fluorination of the alprazolam pharmacophore increases pharmacokinetic parameters including half-life and volume of distribution. The increase in these parameters for flualprazolam and flubromazolam leads to an overall increased exposure in the body and a potential for greater toxicity than alprazolam.

Genetic Variants Associated With Opioid Use Disorder.

Genetics are presumed to contribute 30-40% to opioid use disorder (OUD), allowing for the possibility that genetic markers could be used to identify personal risk for developing OUD. We aimed to test the potential association among 180 candidate single nucleotide polymorphisms (SNPs), 120 of which were related to the dopamine reward pathway and 60 related to pharmacokinetics. Participants were randomly recruited in 2020-2021 in a cross-sectional genetic association study. Self-reported health history including Diagnostic and Statistical Manual of Mental Disorders (DSM-5) OUD criteria and buccal swabs were collected. A total of 1,301 participants were included in the analyses for this study. Of included participants, 250 met the DSM-5 criteria for ever having OUD. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and DSM-5 criteria consistent with OUD. Six SNPs found in four genes were associated with OUD: increased odds with CYP3A5 (rs15524 and rs776746) and DRD3 (rs324029 and rs2654754), and decreased odds with CYP3A4 (rs2740574) and CYP1A2 (rs2069514). Homozygotic CYP3A5 (rs15524 and rs776746) had the highest adjusted odds ratio of 2.812 (95% confidence interval (CI) 1.737, 4.798) and 2.495 (95% CI 1.670, 3.835), respectively. Variants within the dopamine reward and opioid metabolism pathways have significant positive (DRD3 and CYP3A5) and negative (CYP3A4 and CYP1A2) associations with OUD. Identification of these variants provides promising possibilities for genetic prognostic and therapeutic targets for future investigation.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update.

CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).

Pharmacists Leading the Way to Precision Medicine: Updates to the Core Pharmacist Competencies in Genomics.

Genomics is becoming an increasingly important part of health care, and pharmacists are well-positioned to be practice-based leaders in pharmacogenomics and precision medicine. Competencies available through the Genetics/Genomics Competency Center provide a framework for pharmacogenomics instruction in both pharmacy school curricula and continuing education programs. Given the significant advancements in pharmacogenomics over the past decade, the 2019-2020 American Association of Colleges of Pharmacy Pharmacogenomics Special Interest Group updated the pharmacist competencies. The process used a systematic approach which included mapping pharmacogenomics-specific competencies to the entrustable professional activities for pharmacists and seeking consensus from key stakeholders. The result is an expansion to 30 competencies that reflect the contemporary roles pharmacists play in the application of pharmacogenomics in clinical practice. When implemented into curricula, these competencies will ensure that learners are "practice ready" to integrate pharmacogenomics into patient care. Additional postgraduate training is needed for advanced roles in pharmacogenomics implementation, education, and research.

Systematic review of Pharmacogenomics Knowledgebase evidence for pharmacogenomic links to the dopamine reward pathway for heroin dependence.

Genetics play an important role in opioid use disorder (OUD); however, few specific gene variants have been identified. Therefore, there is a need to further understand the pharmacogenomics influences on the pharmacodynamics of opioids. The Pharmacogenomics Knowledgebase (PharmGKB), a database that links genetic variation and drug interaction in the body, was queried to identify polymorphisms associated with heroin dependence in the context of opioid related disorders/OUD. Eight genes with 22 variants were identified as linked to increased risk of heroin dependence, with three genes and variants linked to decreased risk, although the level of evidence was moderate to low. Therefore, continued exploration of biomarker influences on OUD, reward pathways and other contributing circuitries is necessary to understand the true impact of genetics on OUD before integration into clinical guidelines.

Defining the role of pharmacists in medication-related genetic counseling.

There is little question that precision medicine will eventually be the standard of care in treatment with algorithms designed for therapy selection and is already being used in some specialties such as cystic fibrosis and multiple cancer treatments. Genetic counselors are the heart of the treatment team in relation to counseling regarding genetic risk factors and disease states. A framework for treatment within the interdisciplinary team with more defined roles and areas of specialty will need to be in place as this practice approach expands with new data and treatments. Pharmacists are poised to be of great assistance in this matrix as many of these roles are merely an extension of current tasks and responsibilities of pharmacy practice.

Pharmacogenomics in the United States Community Pharmacy Setting: The Clopidogrel-CYP2C19 Example.

Pharmacogenomics (PGx) is expanding across health-care practice settings, including the community pharmacy. In the United States, models of implementation of PGx in the community pharmacy have described independent services and those layered on to medication therapy management. The drug-gene pair of clopidogrel-CYP2C19 has been a focus of implementation of PGx in community pharmacy and serves as an example of the evolution of the application of drug-gene interaction information to help optimize drug therapy. Expanded information related to this drug-gene pair has been provided by the US Food and Drug Administration and clinical PGx guidelines have and continue to be updated to support clinical decision-making. Most recently direct-to-consumer (DTC) PGx has resulted in patient generated sample collection and submission to a genetic testing-related company for analysis, with reporting of genotype and related phenotype information directly to the patient without a health-care professional guiding or even being involved in the process. The DTC testing approach needs to be considered in the development or modification of PGx service models in the community pharmacy setting. The example of clopidogrel-CYP2C19 is discussed and current models of PGx implementation in the community pharmacy in the United States are presented. New approaches to PGx services are offered as implementation continues to evolve and may now include DTC information.

The Expanded Potential Role of Pharmacogenomics.

The topic of phenoconversion was chosen for discussion in this editorial to add to the work presented by Cox and Marshall in this issue of The Senior Care Pharmacist. When considering the increased sensitivity that older patients have to medications, the inclusion of pharmacogenomics (PGx) information can be of great importance. Understanding the consequences of phenoconversion can further expand the role of PGx in patient care.

Pharmacogenomics: A Practical Primer for Senior Care Pharmacists.

Pharmacogenomics (PGx), the study of how an individual's genetic makeup affects his or her response to drugs, is a fast-growing field that gives health care providers a valuable tool to help safely and effectively manage medication. However, few providers have experience in applying the results of PGx tests to their practices, and this can lead to disregarding the data or unnecessarily modifying medication regimens. Pharmacists are uniquely positioned to become wellversed in the interpretation of PGx data, critically evaluating the "green-yellow-red" result categories that seemingly signal "go, caution, stop" regarding the use of a particular medication. Pharmacists also can evaluate genotype and phenotype information, commonly included in PGx laboratory reports, to optimize therapy. Using a case-based approach, this primer is intended to provide consultant pharmacists with practical direction to aid in PGx interpretation that will provide contextappropriate recommendations that contributes to positive patient outcomes.

Expanding Pharmacist and Student Pharmacist Access to Genetics/Genomics/Pharmacogenomics Competency Education.

BACKGROUND: As pharmacogenomics (PGx), a component of genetics/genomics and precision medicine, gains traction in the clinical setting, education of health care providers and health professions students must be made broadly available to improve accessibility of such services to patients. As medication experts with education in pharmacology, pharmacokinetics, and pharmacodynamics, pharmacists must further their education to include pharmacogenomics. Currently, few opportunities exist to gain this type of education, and therefore, these services are not yet broadly available to the public. OBJECTIVE: The specific goal of this study was to evaluate pharmacists' and student pharmacists' self-assessed perception of competence related to genetics, genomics, and pharmacogenomics as presented via an online "pharmacogenomics certification program" (PGx program). DESIGN: The PGx program was delivered online with the content consisting of 3 background lessons and 8 specific drug-gene lessons presented in the context of pharmacist competency statements. In addition, 11 "video modules" with competency-related PGx content were included to provide a comprehensive program. A pre- and post-course survey instrument was used to evaluate the participants' self-assessed perception of competence related to each of 16 statements. RESULTS: One hundred thirty-seven (137) individuals enrolled in and completed the pharmacogenomics certification program. Overall, participants reported self-perceived improved competency as evidenced by the pre-course survey as compared with the post-course survey for each of the 16 competency statements related to genetics/genomics, including pharmacogenomics. Similar results were observed for the subgroups of student pharmacists (n = 63) and pharmacists (n = 74). FUTURE DIRECTION: This study showed that dissemination of genetics/genomics/pharmacogenomics competency statements education can be accomplished via online delivery. This delivery approach can expand genetics/genomics/pharmacogenomics content dissemination. The intent is to reach a broader population of pharmacy students, pharmacists, and other health care providers and health professions students to potentially advance the availability of such services, which can improve the safety and efficacy of medication use for patients.

A review of the influence of functional group modifications to the core scaffold of synthetic cathinones on drug pharmacokinetics.

RATIONALE: The synthetic cathinones are a class of designer drugs of abuse that share a common core scaffold. The pharmacokinetic profiles of the synthetic cathinones vary based on the substitutions to the core scaffold. OBJECTIVES: To provide a summary of the literature regarding the pharmacokinetic characteristics of the synthetic cathinones, with a focus on the impact of the structural modifications to the pharmacokinetics. RESULTS: In many, but not all, instances the pharmacokinetic characteristics of the synthetic cathinones can be reasonably predicted based on the substitutions to the core scaffold. Mephedrone and methylone are chemically alike and have similar Tmax and t1/2 in male rats. MDPV, a structurally distinct synthetic cathinone from mephedrone and methylone, has a lower Tmax and t1/2. Increasing the length of the alkyl chain on the α position of methylone, to produce pentylone, results in increased plasma concentrations and longer t1/2. Metabolism of the synthetic cathinones is reasonably predictable based on the chemical structure, and several phase I metabolites retain pharmacodynamic activity. CYP2D6 is implicated in the metabolism of all of the synthetic cathinones, and other P450s (CYP1A2, CYP2B6, and CYP2C19) are known to contribute variably to the metabolism of specific synthetic cathinones. CONCLUSIONS: Continued research will lead to a better understanding of the pharmacokinetic changes associated with structural modifications to the cathinone scaffold, and potentially in the long range, enhanced overdose and addiction therapy. Additionally, the areas of polydrug use and pharmacogenetics have been largely overlooked with regard to synthetic cathinones.

Pharmacokinetic data of synthetic cathinones in female Sprague-Dawley rats.

The synthetic cathinones methylone, butylone, and pentylone differ from each other through the one carbon lengthening of the α-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3) while 3,4-methylenedioxymethamphetamine (MDMA) differs from methylone by a single oxygen atom. Studies with MDMA, suggests that there may be male and female pharmacokinetic and pharmacodynamic differences. In the present study, we present the plasma pharmacokinetic data relative to a 20 mg/kg, subcutaneous doses of methylone, butylone and pentylone in female Sprague-Dawley rats. Briefly, plasma samples were collected via a jugular vein cannula, purified, and analyzed using a HPLC system. While we have previously reported on the consistent relationship between structure and pharmacokinetics of these synthetic cathinones in male, Sprague-Dawley rats (Grecco and Sprague, 2016), this data set suggests that there is no consistent relationship of chemical structure and pharmacokinetics of methylone, butylone and pentylone in female Sprague-Dawley rats. The findings from the present study further emphasize the need for the inclusion of female subjects in the pharmacokinetic studies of synthetic cathinones as it is very possible male-female differences may exist in rodent models.

Systematic evaluation of clinical practice guidelines for pharmacogenomics.

AIM: To systematically assess methodological quality of pharmacogenomics clinical practice guidelines. METHODS: Guidelines published through 2017 were reviewed by at least three independent reviewers using the AGREE II instrument, which consists of 23 items grouped into 6 domains and 2 items representing an overall assessment. Items were assessed on a seven-point rating scale, and aggregate quality scores were calculated. RESULTS: 31 articles were included. All guidelines were published as peer-reviewed articles and 90% (n = 28) were endorsed by professional organizations. Mean AGREE II domain scores (maximum score 100%) ranged from 46.6 ± 11.5% ('applicability') to 78.9 ± 11.4% ('clarity of presentation'). Median overall quality score was 72.2% (IQR: 61.1-77.8%). CONCLUSION: Quality of pharmacogenomics guidelines was generally high, but variable, for most AGREE II domains.