Pharmacogenomics-assisted schizophrenia management: A hybrid type 2 effectiveness-implementation study protocol to compare the clinical utility, cost-effectiveness, and barriers.

OBJECTIVES: The response to antipsychotic therapy is highly variable. Pharmacogenomic (PGx) factors play a major role in deciding the effectiveness and safety of antipsychotic drugs. A hybrid type 2 effectiveness-implementation research will be conducted to evaluate the clinical utility (safety and efficacy), cost-effectiveness, and facilitators and barriers in implementing PGx-assisted management compared to standard of care in patients with schizophrenia attending a tertiary care hospital in eastern India. METHODS: In part 1, a randomized controlled trial will be conducted. Adult patients with schizophrenia will be randomized (2: 1) to receive PGx-assisted treatment (drug and regimen selection depending on the results of single-nucleotide polymorphisms in genes DRD2, HTR1A, HTR2C, ABCB1, CYP2D6, CYP3A5, and CYP1A2) or the standard of care. Serum drug levels will be measured. The patients will be followed up for 12 weeks. The primary endpoint is the difference in the Udvalg for Kliniske Undersøgelser Side-Effect Rating Scale score between the two arms. In part 2, the cost-effectiveness of PGx-assisted treatment will be evaluated. In part 3, the facilitators and barriers to implementing PGx-assisted treatment for schizophrenia will be explored using a qualitative design. EXPECTED OUTCOME: The study findings will help in understanding whether PGx-assisted management has a clinical utility, whether it is cost-effective, and what are the facilitators and barriers to implementing it in the management of schizophrenia. TRIAL REGISTRATION: The study has been registered with the Clinical Trials Registry-India (CTRI/2023/08/056210).

[The pharmacogenetics as integral part of personalized medicine: problems and prospects].

The article considers issues of implementation into clinical practice the principles of 5P medicine in its part of individualization of therapeutic tactics considering genetic characteristics of patients. The analysis of studies concerning influence of allelic variations on metabolism, safety and tolerance of the most often prescribed medicinal preparations was implemented. The main assumptions of pharmacogenomics were considered. Despite broad perspective of applying obtained data in clinical practice, there are a number of unresolved problems related to accessibility of genetic testing to population, ambiguity of approaches to interpretation of obtaining results, ethical issues and legal regulation.

The role of community engagement in promoting research participants' understanding of pharmacogenomic research results: Perspectives of stakeholders involved in HIV/AIDS research and treatment.

Community engagement (CE) is praised to be a powerful vehicle in empowering communities with knowledge and skills to make informed decisions for better health care. Several CE approaches have been proposed to improve participants' and research communities' understanding of genomic research including pharmacogenomic information and results. However, there is limited literature on how these approaches can be used to communicate findings of pharmacogenomic research to communities of people living with HIV. This study explored stakeholders' perspectives on the role of community engagement in promoting understanding of pharmacogenomic research results among people living with HIV. We adopted a qualitative approach that involved 54 stakeholders between September 2021 and February 2022. We held five focus group discussions among 30 community representatives from five research institutions, 12 key informant interviews among researchers, and 12 in-depth interviews among ethics committee members. A thematic approach was used to analyze the results. Five themes merged from this data and these included (i) benefits of engaging communities prior to returning individual pharmacogenomic research results to participants. (ii) Obtaining community consensus on the kinds of pharmacogenomic results to be returned. (iii) Opinions on how pharmacogenomic research information and results should be communicated at community and individual levels. (iv) Perceived roles of community stakeholders in promoting participants' understanding and utilization of pharmacogenomic research results. (v) Perceived challenges of engaging communities when returning individual results to research participants. Stakeholders opined that CE facilitates co-learning between researchers and research communities. Researchers can adapt existing CE approaches that are culturally acceptable for meaningful engagement with minimal ethical and social risks when communicating pharmacogenomic research results. CE approaches can facilitate understanding of pharmacogenomic research and findings among research participants and communities. Therefore, if creatively adapted, existing and new CE approaches can enable researchers to communicate simple and understandable results of pharmacogenomic research.

Treatment for Resistant Hypertension Under the Guidance of Pharmacogenomics: A Randomised Controlled Open-Label Trial.

OBJECTIVE: To evaluate the efficacy and safety of pharmacogenomics (PGx)-guided treatment in individuals with resistant hypertension (RH). STUDY DESIGN: Randomised controlled open-label study. Place and Duration of the Study: Department of Cardiology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China, from June 2019 to November 2021. METHODOLOGY: The study assigned RH patients to two groups. The intervention group (IG) received 12 weeks of PGx-guided treatment, while the control group (CG) followed a consensus-based approach. Examining 10 genes and their alleles with 31 antihypertensive drugs in the IG, the study provided specific medication advice. The primary outcome measured the difference in office systolic blood pressure (SBP) change from baseline at 12 weeks. Secondary outcomes included changes in diastolic blood pressure (DBP), hepatic and renal function, and major adverse cardiovascular events. RESULTS: Fifty-nine patients from the First Hospital of China Medical University participated, with 29 in the IG and 30 in the CG. Significant differences were noted in SBP reduction (IG: 31.26 ± 18.64 mmHg; CG: 14.61 ± 17.74 mmHg; p=0.001) and DBP reduction (IG: 19.61 ± 17.32 mmHg; CG: 7.81 ± 11.23 mmHg; p = 0.003) after 12 weeks. One IG patient had a heart attack, and one CG subject developed heart failure. At week 12, hepatic insufficiency was observed in one IG patient and six CG patients, while renal insufficiency occurred in five patients of both groups. CONCLUSION: Treatment guided by PGx demonstrated significant reductions in both SBP and DBP compared to consensus-based treatment. KEY WORDS: Resistant hypertension, Treatment, Pharmacogenomics, Clinical study.

Pharmacogenomic profiling of intra-tumor heterogeneity using a large organoid biobank of liver cancer.

Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and ß-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.

Pharmacogenomic study-A pilot study of the effect of pharmacogenomic phenotypes on the adequate dosing of verapamil for migraine prevention.

OBJECTIVE: To investigate factors affecting the efficacy and tolerability of verapamil for migraine prevention using individual pharmacogenomic phenotypes. BACKGROUND: Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual. METHODS: This is a retrospective chart review examining adults with existing pharmacogenomic reports at Mayo Clinic who had used verapamil for migraine. Effects of six cytochrome P450 phenotypes on the doses of verapamil for migraine prevention were assessed. RESULTS: Our final analysis included 33 migraine patients (82% with aura). The mean minimum effective and maximum tolerable doses of verapamil were 178.2(20-320) mg and 227.9(20-480) mg. A variety of CYP2C9, CYP2D6, and CYP3A5 phenotypes were found, without significant association with the verapamil doses after adjusting for age, sex, body mass index, and smoking status. CONCLUSIONS: We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.

Influence of pharmacogenomic polymorphisms on allopurinol-induced cutaneous adverse drug reactions in Thai patients.

BACKGROUND: Allopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. METHODS: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls. RESULTS: Out of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2-266.8; P = 1.9 × 10- 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3-670.5 and p-value = 1.7 × 10- 27). CONCLUSIONS: Thus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.

Herramientas para un ajuste de dosis de tacrolimus más personalizado en el seguimiento de los pacientes con transplante renal. Fenotipo metabolizador según polimorfismos genéticos del CYP3A vs. el cociente concentración-dosis / Tools for a personalized tacrolimus dose adjustment in the follow-up of renal transplant recipients: Metabolizing phenotype according to CYP3A genetic polymorphisms versus concentration–dose ratio

Antecedentes y justificación: La estrategia de la aproximación concentración-dosis (C/D) y los distintos perfiles del tacrolimus (Tac), según los polimorfismos del citocromo P450 (CYPs) se centran en el metabolismo de Tac y se plantean como herramientas para el seguimiento de los pacientes trasplantados. El objetivo de este estudio es comparar la exposición al Tac analizado según ambas estrategias. Materiales y métodos: Se han incluido 425 pacientes trasplantados renales. El cálculo del cociente concentración Tac/dosis (C/D) permitió dividir la población en terciles y clasificar los pacientes según su tasa de metabolismo del Tac en tres grupos (rápida, intermedia y lenta). Con base en los polimorfismos del CYP3A4 y A5, los pacientes se agruparon en metabolizadores rápidos (portadores del CYP3A5*1 y CYP34A *1/*1), intermedios (CYP3A5*3/3 y CYP3A4*1/*1) y lentos (CYP3A5 *3/*3 y portadores del CYP3A4*22). Resultados: Al comparar los pacientes de cada grupo metabolizador según los dos criterios, coincidieron 47% (65/139) de los metabolizadores rápidos, 85% (125/146) de los intermedios y solo 12% (17/140) de los lentos. Se observaron concentraciones de Tac estadísticamente menores en los metabolizadores rápidos y concentraciones mayores en los lentos, comparándolos con el grupo intermedio según el cociente C/D o según polimorfismos. Los metabolizadores rápidos requirieron alrededor de 60% más de dosis de Tac que los intermedios a lo largo del seguimiento, mientras que los lentos aproximadamente 20% menos de dosis que los intermedios. Los metabolizadores rápidos clasificados por ambos criterios presentan un porcentaje mayor de veces con valores de concentración de Tac en sangre infraterapéuticos... (AU)

Background and justification: The strategy of the concentration–dose (C/D) approach and the different profiles of tacrolimus (Tac) according to the cytochrome P450 polymorphisms (CYPs) focus on the metabolism of Tac and are proposed as tools for the follow-up of transplant patients. The objective of this study is to analyse both strategies to confirm whether the stratification of patients according to the pharmacokinetic behaviour of C/D corresponds to the classification according to their CYP3A4/5 cluster metabolizer profile. Materials and methods: Four hundred and twenty-five kidney transplant patients who received Tac as immunosuppressive treatment have been included. The concentration/dose ratio (C/D) was used to divided patients in terciles and classify them according to their Tac metabolism rate (fast, intermediate, and slow). Based on CYP3A4 and A5 polymorphisms, patients were classified into three metabolizer groups: fast (CYP3A5*1 and CYP34A*1/*1 carriers), intermediate (CYP3A5*3/3 and CYP3A4*1/*1) and slow (CYP3A5*3/*3 and CYP3A4*22 carriers). Results: When comparing patients included in each metabolizer group according to C/D ratio, 47% (65/139) of the fast metabolizers, 85% (125/146) of the intermediate and only 12% (17/140) of the slow also fitted in the homonym genotype group. Statistically lower Tac concentrations were observed in the fast metabolizers group and higher Tac concentrations in the slow metabolizers when compared with the intermediate group both in C/D ratio and polymorphisms criteria. High metabolizers required approximately 60% more Tac doses than intermediates throughout follow-up, while poor metabolizers required approximately 20% fewer doses than intermediates. Fast metabolizers classified by both criteria presented a higher percentage of times with sub-therapeutic blood Tac concentration values... (AU)

Cost-utility analysis of pharmacogenomics-guided tacrolimus treatment in Austrian kidney transplant recipients participating in the U-PGx PREPARE study.

Chronic kidney disease (CKD) is a global health issue. Kidney failure patients may undergo a kidney transplantation (KTX) and prescribed an immunosuppressant medication i.e., tacrolimus. Tacrolimus' efficacy and toxicity varies among patients. This study investigates the cost-utility of pharmacogenomics (PGx) guided tacrolimus treatment compared to the conventional approach in Austrian patients undergone KTX, participating in the PREPARE UPGx study. Treatment's effectiveness was determined by mean survival, and utility values were based on a Visual Analog Scale score. Incremental Cost-Effectiveness Ratio was also calculated. PGx-guided treatment arm was found to be cost-effective, resulting in reduced cost (3902 euros less), 6% less hospitalization days and lower risk of adverse drug events compared to the control arm. The PGx-guided arm showed a mean 0.900 QALYs (95% CI: 0.862-0.936) versus 0.851 QALYs (95% CI: 0.814-0.885) in the other arm. In conclusion, PGx-guided tacrolimus treatment represents a cost-saving option in the Austrian healthcare setting.

Implementing Whole Genome Sequencing (WGS) in Clinical Practice: Advantages, Challenges, and Future Perspectives.

The integration of whole genome sequencing (WGS) into all aspects of modern medicine represents the next step in the evolution of healthcare. Using this technology, scientists and physicians can observe the entire human genome comprehensively, generating a plethora of new sequencing data. Modern computational analysis entails advanced algorithms for variant detection, as well as complex models for classification. Data science and machine learning play a crucial role in the processing and interpretation of results, using enormous databases and statistics to discover new and support current genotype-phenotype correlations. In clinical practice, this technology has greatly enabled the development of personalized medicine, approaching each patient individually and in accordance with their genetic and biochemical profile. The most propulsive areas include rare disease genomics, oncogenomics, pharmacogenomics, neonatal screening, and infectious disease genomics. Another crucial application of WGS lies in the field of multi-omics, working towards the complete integration of human biomolecular data. Further technological development of sequencing technologies has led to the birth of third and fourth-generation sequencing, which include long-read sequencing, single-cell genomics, and nanopore sequencing. These technologies, alongside their continued implementation into medical research and practice, show great promise for the future of the field of medicine.

A New Cloud-Native Tool for Pharmacogenetic Analysis.

BACKGROUND: The advancement of next-generation sequencing (NGS) technologies provides opportunities for large-scale Pharmacogenetic (PGx) studies and pre-emptive PGx testing to cover a wide range of genotypes present in diverse populations. However, NGS-based PGx testing is limited by the lack of comprehensive computational tools to support genetic data analysis and clinical decisions. METHODS: Bioinformatics utilities specialized for human genomics and the latest cloud-based technologies were used to develop a bioinformatics pipeline for analyzing the genomic sequence data and reporting PGx genotypes. A database was created and integrated in the pipeline for filtering the actionable PGx variants and clinical interpretations. Strict quality verification procedures were conducted on variant calls with the whole genome sequencing (WGS) dataset of the 1000 Genomes Project (G1K). The accuracy of PGx allele identification was validated using the WGS dataset of the Pharmacogenetics Reference Materials from the Centers for Disease Control and Prevention (CDC). RESULTS: The newly created bioinformatics pipeline, Pgxtools, can analyze genomic sequence data, identify actionable variants in 13 PGx relevant genes, and generate reports annotated with specific interpretations and recommendations based on clinical practice guidelines. Verified with two independent methods, we have found that Pgxtools consistently identifies variants more accurately than the results in the G1K dataset on GRCh37 and GRCh38. CONCLUSIONS: Pgxtools provides an integrated workflow for large-scale genomic data analysis and PGx clinical decision support. Implemented with cloud-native technologies, it is highly portable in a wide variety of environments from a single laptop to High-Performance Computing (HPC) clusters and cloud platforms for different production scales and requirements.

Forging the path to precision medicine in Qatar: a public health perspective on pharmacogenomics initiatives.

Pharmacogenomics (PGx) is an important component of precision medicine that promises tailored treatment approaches based on an individual's genetic information. Exploring the initiatives in research that help to integrate PGx test into clinical setting, identifying the potential barriers and challenges as well as planning the future directions, are all important for fruitful PGx implementation in any population. Qatar serves as an exemplar case study for the Middle East, having a small native population compared to a diverse immigrant population, advanced healthcare system, national genome program, and several educational initiatives on PGx and precision medicine. This paper attempts to outline the current state of PGx research and implementation in Qatar within the global context, emphasizing ongoing initiatives and educational efforts. The inclusion of PGx in university curricula and healthcare provider training, alongside precision medicine conferences, showcase Qatar's commitment to advancing this field. However, challenges persist, including the requirement for population specific implementation strategies, complex genetic data interpretation, lack of standardization, and limited awareness. The review suggests policy development for future directions in continued research investment, conducting clinical trials for the feasibility of PGx implementation, ethical considerations, technological advancements, and global collaborations to overcome these barriers.

Utilizing Pharmacogenomics Results to Guide Antidepressant Selection: A Case Report.

The case discussion demonstrates the benefit of using Pharmacogenomic (PGx) results to aid in the selection of antidepressant therapy and improve response to treatment. Nearly half of patients diagnosed with major depressive disorder fail initial therapy and may require multiple trials of antidepressants. Genetic variation in several metabolic enzymes contribute to the variable response to antidepressant therapy. PGx testing provides an opportunity to inform antidepressant selection and optimize therapeutic outcomes, while minimizing risk of adverse events. A 79-year-old female who had been experiencing a suboptimal response to escitalopram following dose escalation over a period of three years was referred for a PGx consultation. A clinical pharmacist assessed significant drug-gene, drug-drug, and drug-drug-gene interactions, and relevant clinical information to recommend alternative antidepressant therapy, which resulted in mood improvement.

Utilizing Pharmacogenomics Results to Improve Statin-Associated Muscle Symptoms.

The objective of this aims to demonstrate the advantage of a pharmacogenomics (PGx)-informed medication review in mitigating adverse drug events (ADEs) and optimizing therapeutic outcomes. PGx testing and PGx-informed medication reviews assist in mitigating ADEs. PGx testing was performed on a 68-year-old male presenting with uncontrolled chronic pain. The PGx results highlighted a drug-gene interaction, aiding in identification of the increased risk of statin-associated muscle symptoms (SAMS) attributing to uncontrolled chronic pain. This patient case report illustrates how incorporating PGx results can help improve chronic pain and mitigate ADEs, such as SAMS.

Pharmacogenomics in Clinical Practice for Older People.

Older people are over-represented among individuals that experience adverse drug reactions (ADR) and adverse drug events (ADE). Furthermore, older people are over-represented among individuals that visit emergency departments and are hospitalized because of ADRs. Moreover, older people are overrepresented among those who suffer ADEs while hospitalized. Finally, older people are among those most likely to have an anaphylactic response to prescription medications. Therefore, older people are prime candidates for efforts aimed at optimizing pharmacotherapeutic outcomes. Pharmacogenomics is an approach of using genetic data to optimize pharmacotherapeutic outcomes. Over the last two decades, pharmacogenomics grew from research initiatives into the current environment of pharmacogenomics implementation. Specifically, implementing pharmacogenomics into clinical settings or within health care systems has proven beneficial in optimizing pharmacotherapeutic outcomes. Therefore, pharmacists focused on optimizing pharmacotherapeutic outcomes for older people should be aware of the approaches to and resources available for implementing pharmacogenomics. KEY WORDS: Drug labeling biomarkers, Genes, Older adults, Pharmacogenomics.

Uncoupling of Cytochrome P450 2B6 and stimulation of reactive oxygen species production in pharmacogenomic alleles affected by interethnic variability.

Cytochrome P450 mediated substrate metabolism is generally characterized by the formation of reactive intermediates. In vitro and in vivo reaction uncoupling, results in the accumulation and dissociation of reactive intermediates, leading to increased ROS formation. The susceptibility towards uncoupling and altered metabolic activity is partly modulated by pharmacogenomic alleles resulting in amino acid substitutions. A large variability in the prevalence of these alleles has been demonstrated in CYP2B6, with some being predominantly unique to African populations. The aim of this study is to characterize the uncoupling potential of recombinant CYP2B6*1, CYP2B6*6 and CYP2B6*34 metabolism of specific substrates. Therefore, functional effects of these alterations on enzyme activity were determined by quantification of bupropion, efavirenz and ketamine biotransformation using HPLC-MS/MS. Determination of H2O2 levels was performed by the AmplexRed/horseradish peroxidase assay. Our studies of the amino acid substitutions Q172H, K262R and R487S revealed an exclusive use of the peroxide shunt for the metabolism of bupropion and ketamine by CYP2B6*K262R. Ketamine was also identified as a trigger for the peroxide shunt in CYP2B6*1 and all variants. Concurrently, ketamine acted as an uncoupler for all enzymes. We further showed that the expressed CYP2B6*34 allele results in the highest H2O2 formation. We therefore conclude that the reaction uncoupling and peroxide shunt are directly linked and can be substrate specifically induced with K262R carriers being most likely to use the peroxide shunt and R487S carrier being most prone to reaction uncoupling. This elucidates the functional diversity of pharmacogenomics in drug metabolism and safety.

Effects of pharmacogenetics on pharmacokinetics and toxicity of doxorubicin in Egyptian breast cancer patients.

This study investigates the impact of single nucleotide polymorphisms in genes (SLC22A16 and CBR1) involved in the pharmacokinetics and toxicity of doxorubicin (DOX) in Egyptian female patients with breast cancer.Patients administered DOX (60 mg/m2) for 4 cycles every 3 weeks. The peak DOX plasma concentration was measured using a validated chromatographic method. The genotyping for the selected SNPs, SLC22A16 T > C (rs714368), and CBR1 C > T (rs20572), was performed by RT-PCR. Patients were monitored for hematological and cardiac toxicities.The variant carriers of CBR1 C > T (rs20572) exhibited significantly higher DOX concentration, but no significant association to DOX-induced hematological toxicity. On the other hand, SLC22A16 T > C (rs714368) had no significant influence on DOX plasma concentration, but was significantly correlated with lower risk of neutropenia (OR 0.31, 95% CI 0.12-0.75, p = 0.01) and leukopoenia (OR 0.18, 95% CI 0.07-0.5, p = 0.001). DOX-related cardiotoxicity was correlated with the cumulative dose of DOX (R = 0.238, p = 0.017), but not with any of the two examined SNPs.Genetic polymorphisms in SLC22A16 and CBR1 may explain the inter-individual variations in DOX pharmacokinetics and toxicity. Using pharmacogenetic testing is important to customise drug therapy for cancer patients treated with anthracyclines.