Pharmacogenomics. 2025 Mar 31:1-7. doi: 10.1080/14622416.2025.2478810. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to identify the impact of CYP2C19 polymorphism testing on clinical outcomes in patients who have undergone carotid artery stenting (CAS).

METHODS: This was a single-center retrospective cohort study. CYP2C19 polymorphisms were identified based on the presence of two normal functional alleles in normal metabolizers (NMs), a normal functional allele and a nonfunctional allele in intermediate metabolizers and two nonfunctional alleles in poor metabolizers. Patients were recommended for the CYP2C19 polymorphism testing followed by the change in dual antithrombotic drugs (DAPT) at the discretion of the supervising physician. The primary clinical endpoint was stent thrombosis (ST). Logistic regression was used to evaluate the relative risk of clinical outcomes.

RESULTS: A total of 273 patients were included. The relative risk of ST was not reduced in patients who underwent CYP2C19 polymorphism testing than in patients without this test (3.1% vs. 3.9%, OR = 0.914, 95% CI = 0.218-3.841). The ST in NMs and non-NMs was 3.4% and 2.9%, respectively, and showing no reduction in NMs (OR = 1.145, 95% CI = 0.162-8.105). Changing DAPT did not reduce the relative risk of ST compared with non-changing (2.3% vs. 3.2%, OR = 1.604, 95% CI = 0.024-107.033).

CONCLUSIONS: CYP2C19 polymorphism was not related to stent thrombosis in patients with CAS.

PMID:40162622 | DOI:10.1080/14622416.2025.2478810

J Cell Mol Med. 2025 Apr;29(7):e70511. doi: 10.1111/jcmm.70511.

ABSTRACT

Valve interstitial cells (VICs) play a critical role in aortic valve calcification and angiogenic processes associated with calcific aortic valve stenosis (CAVS). Within the same valve, VICs from differently calcified regions can exhibit diverse phenotypic and functional properties. We hypothesised that VICs isolated from noncalcified (NC-VICs) and calcified (C-VICs) areas of human aortic valves possess distinct angiogenic characteristics. In this study, we isolated C-VICs and NC-VICs from 23 valves obtained after aortic valve replacement due to CAVS. Both VIC types exhibited similar phenotypes in culture, characterised by morphology, expression of mesenchymal/fibroblastic markers, proliferation and osteogenic differentiation. No significant differences were observed in the secretion of angiogenic factors, including VEGF-A, Ang-1, Ang-2, PlGF, bFGF between NC-VICs and C-VICs. However, when co-injected with endothelial colony-forming cells (ECFCs) into Matrigel implants in vivo in mice, implants containing NC-VICs showed significantly higher microvessel density compared to those with C-VICs (p < 0.001). Additionally, NC-VICs co-cultured with ECFCs expressed significantly higher levels of the perivascular markers αSMA and calponin compared to C-VICs (p < 0.001 and p < 0.05, respectively). In conclusion, our study reveals the heterogeneity in VIC plasticity within the aortic valve during CAVS. The diminished capacity of VICs from calcified areas to differentiate into perivascular cells suggests a loss of function as valve disease progresses. Furthermore, the ability of VICs to undergo perivascular differentiation may provide insights into valve homeostasis, angiogenesis and the exacerbation of calcification.

PMID:40159645 | DOI:10.1111/jcmm.70511

Parkinsonism Relat Disord. 2025 Mar 20:107804. doi: 10.1016/j.parkreldis.2025.107804. Online ahead of print.

NO ABSTRACT

PMID:40157818 | DOI:10.1016/j.parkreldis.2025.107804

Mol Cell Neurosci. 2025 Mar 27:104006. doi: 10.1016/j.mcn.2025.104006. Online ahead of print.

ABSTRACT

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and oxidative stress represent important mechanisms that have been implicated in etiopathology of depression. Although first antidepressants were introduced in clinical practice more than six decades ago, approximately 30 % of patients with a diagnosis of depression show treatment resistance. A noncompetitive N-methyl-d-aspartate receptor antagonist ketamine has shown promising rapid antidepressant effects and has been approved for treatment-resistant depression (TRD). In the present study, we investigated antioxidant and antidepressant-like activity of a single subanesthetic dose of ketamine (10 mg/kg, ip) in a rodent model of TRD induced by adrenocorticotropic hormone (10 μg ACTH/day, sc, 21 days). Behavioral assessment was performed, and plasma biomarkers of oxidative stress and DNA damage in peripheral blood lymphocytes (PBLs) were determined. We observed that ACTH produced depressive-like behavior and significant increase in superoxide anion (O2·-), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and total oxidant status (TOS) in male Wistar rats. This effect was accompanied by reduced activity of antioxidant enzymes - superoxide dismutase (SOD) and paraoxonase1 (PON1) in plasma and increase in DNA damage in PBLs. In the described model of TRD, we have demonstrated antidepressant effects of ketamine for the first time. Our results reveal that ketamine was effective in reducing O2.-, AOPP, MDA and TOS, while enhancing SOD and PON1 activity in ACTH-rats. Collectively, our study sheds light on molecular mechanisms implicated in antioxidant activity of ketamine, thus incentivizing further investigation of its effects on ROS metabolism and antioxidant defenses in clinical trials, particularly in depression.

PMID:40157469 | DOI:10.1016/j.mcn.2025.104006

J Pharm Sci. 2025 Mar 26:103772. doi: 10.1016/j.xphs.2025.103772. Online ahead of print.

ABSTRACT

OATP2B1, encoded by SLCO2B1, is a drug transporter expressed widely throughout the body in tissues such as the intestine and liver. Genetic variation of this transporter may lead to altered disposition of OATP2B1 substrate drugs, but especially the effects of rare variants are poorly understood. The aim of this study was to characterize the effects of naturally occurring missense single nucleotide variants of SLCO2B1 (c.601G>A, c.935G>A, c.953C>T, c.1175C>, c.1457C>T, c.1559G>C, c.1596C>A, and the c.601G>A + c.935G>A haplotype) on the in vitro functionality of OATP2B1. To characterize transport activity, cellular uptake of dibromofluorescein, 5-carboxyfluorescein, estrone sulfate, and rosuvastatin was compared in OATP2B1 reference- and variant-expressing HEK293 cells. The abundance of OATP2B1 variants in HEK293 crude membrane preparations was quantified with LC-MS/MS-based quantitative targeted absolute proteomics analysis. Variant c.1559G>C impaired OATP2B1-mediated uptake of all tested substrates almost completely, but protein abundance was not reduced to the same extent. Other studied variants had comparable or only modestly reduced protein abundance and transport function compared to reference OATP2B1. These results can be utilized to understand findings from clinical pharmacogenetic studies. More importantly, the results can aid in predicting the consequences of rare variants, such as the loss-of-function variant c.1559G>C, which can be difficult to detect in clinical studies.

PMID:40154787 | DOI:10.1016/j.xphs.2025.103772

Semin Cancer Biol. 2025 Mar 26:S1044-579X(25)00051-3. doi: 10.1016/j.semcancer.2025.03.002. Online ahead of print.

ABSTRACT

Pancreatic cancers have high mortality and rising incidence rates which may be related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and obesity rates. Recent data also suggest a role for the gut microbiome in the development of pancreatic cancer. Here, we review the experimental and observational evidence for the roles of the oral, gut and intratumoural microbiomes, impaired gut barrier function and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to pancreatic disease with a focus on pancreatic ductal adenocarcinoma initiation and progression. We also highlight some emerging gut microbiome editing techniques currently being investigated in the context of pancreatic disease. Notably, while the gut microbiome is significantly altered in PDAC and its precursor diseases, its utility as a diagnostic and prognostic tool is hindered by a lack of reproducibility and the potential for reverse causality in case-control cohorts. Future research should emphasise longitudinal and mechanistic studies as well as integrating lifestyle exposure and multi-omics data to unravel complex host-microbiome interactions. This will allow for deeper aetiologic and mechanistic insights that can inform treatments and guide public health recommendations.

PMID:40154652 | DOI:10.1016/j.semcancer.2025.03.002

Biomedicines. 2025 Feb 21;13(3):553. doi: 10.3390/biomedicines13030553.

ABSTRACT

Background/Objectives: The COVID-19 pandemic resulted in 675 million cases and 6.9 million deaths by 2022. Despite substantial declines in case fatalities following widespread vaccination campaigns, the threat of future coronavirus outbreaks remains a concern. Current treatments for COVID-19 have been repurposed from existing therapies for other infectious and non-infectious diseases. Emerging evidence suggests a role for genetic factors in both susceptibility to SARS-CoV-2 infection and response to treatment. However, comprehensive studies correlating clinical outcomes with genetic variants are lacking. The main aim of our study is the identification of host genetic biomarkers that predict the clinical outcome of COVID-19 pharmacological treatments. Methods: In this study, we present findings from GWAS and candidate gene and pathway enrichment analyses leveraging diverse patient samples from the Spanish Coalition to Unlock Research of Host Genetics on COVID-19 (SCOURGE), representing patients treated with immunomodulators (n = 849), corticoids (n = 2202), and the combined cohort of both treatments (n = 2487) who developed different outcomes. We assessed various phenotypes as indicators of treatment response, including survival at 90 days, admission to the intensive care unit (ICU), radiological affectation, and type of ventilation. Results: We identified significant polymorphisms in 16 genes from the GWAS and candidate gene studies (TLR1, TLR6, TLR10, CYP2C19, ACE2, UGT1A1, IL-1α, ZMAT3, TLR4, MIR924HG, IFNG-AS1, ABCG1, RBFOX1, ABCB11, TLR5, and ANK3) that may modulate the response to corticoid and immunomodulator therapies in COVID-19 patients. Enrichment analyses revealed overrepresentation of genes involved in the innate immune system, drug ADME, viral infection, and the programmed cell death pathways associated with the response phenotypes. Conclusions: Our study provides an initial framework for understanding the genetic determinants of treatment response in COVID-19 patients, offering insights that could inform precision medicine approaches for future epidemics.

PMID:40149530 | DOI:10.3390/biomedicines13030553

Genes (Basel). 2025 Mar 17;16(3):349. doi: 10.3390/genes16030349.

ABSTRACT

In an obesogenic environment, such as the one we have been experiencing in recent decades, epigenetics provides answers to the relationship between hereditary and environmentally acquired patterns that have significantly contributed to the global rise in obesity prevalence. MicroRNA (miRNA) constitutes a diminutive non-coding small RNA molecule, 20 to 24 nucleotides in length, that functions as a regulator of gene regulation at the post-translational level. Circulating miRNAs (c-miRNAs) have been detected in multiple body fluids, including blood, plasma, serum, saliva, milk from breastfeeding mothers, and urine. These molecules hold significant therapeutic value and serve as extracellular biomarkers in metabolic diseases. They aid in the diagnosis and tracking of therapy responses, as well as dietary and physical habit modifications. Researchers have studied c-miRNAs as potential biomarkers for diagnosing and characterizing systemic diseases in people of all ages and backgrounds since then. These conditions encompass dyslipidemia, type 2 diabetes mellitus (T2DM), cardiovascular risk, metabolic syndrome, cardiovascular diseases, and obesity. This review therefore analyzes the usefulness of c-miRNAs as therapeutic markers over the past decades. It also provides an update on c-miRNAs associated with general obesity and overweight, as well as with the most prevalent pathologies in the adult population. It also examines the effect of different nutritional approaches and physical activity regarding the activity of miRNAs in circulation in adults with overweight or general obesity. All of this is done with the aim of evaluating their potential use as biomarkers in various research contexts related to overweight and obesity in adults.

PMID:40149500 | DOI:10.3390/genes16030349

Genes (Basel). 2025 Mar 6;16(3):314. doi: 10.3390/genes16030314.

ABSTRACT

Chronic Obstructive Pulmonary Disease (COPD) manifests as a genetically diverse and intricate lung condition with various subtypes. The development of the disease and response to treatment are influenced by the interplay between genetic and environmental factors. The predominant therapeutic approaches include bronchodilator therapy and corticosteroid treatment. Studies in COPD pharmacogenetics involve genome-wide association (GWA) studies, gene profiling, whole-genome sequencing, and other omics-based investigations. Many of these investigations have focused on the association between genetic variations and the response to β2 agonist treatment. Additionally, several studies have explored the impact of gene variations on the response to inhaled corticosteroid (ICS) treatment, with a specific focus on polymorphisms in the glucocorticoid receptor (GR) signaling pathway. However, a significant challenge lies in the inconclusive or inconsistent results of these pharmacogenetic studies, underscoring the research community's struggle to provide sufficient evidence for the clinical implementation of COPD pharmacogenetics. To address these challenges, further research and larger genome-wide studies are essential. These efforts aim to uncover additional COPD subtypes, identify predictors of treatment response, and discover novel genetic markers for COPD. The integration of genomics, detailed evaluations such as chest CT scans, spirometry tests, and blood analyses, along with DNA collection in clinical research, is critical for translating COPD pharmacogenetics into clinical practice. Furthermore, advancing our understanding of the complex interactions between genetics, phenotypes, and environmental factors will be pivotal for improving individualized prognostic assessments and enhancing treatment outcomes in COPD.

PMID:40149465 | DOI:10.3390/genes16030314

Genes (Basel). 2025 Feb 24;16(3):265. doi: 10.3390/genes16030265.

ABSTRACT

Background/Objectives: The accurate prediction of adverse drug reactions (ADRs) to oncological treatments still poses a clinical challenge. Chemotherapy is usually selected based on clinical trials that do not consider patient variability in ADR risk. Consequently, many patients undergo multiple treatments to find the appropriate medication or dosage, enhancing ADR risks and increasing the chance of discontinuing therapy. We first aimed to develop a pharmacogenetic model for predicting chemotherapy-induced ADRs in cancer patients (the ANTIBLASTIC DRUG MULTIPANEL PLATFORM) and then to assess its feasibility and validate this model in patients with non-small-cell lung cancer (NSCLC) undergoing oncological treatments. Methods: Seventy NSCLC patients of all stages that needed oncological treatment at our facility were enrolled, reflecting the typical population served by our institution, based on geographic and demographic characteristics. Treatments followed existing guidelines, and patients were continuously monitored for adverse reactions. We developed and used a multipanel platform based on 326 SNPs that we identified as strongly associated with response to cancer treatments. Subsequently, a network-based algorithm to link these SNPs to molecular and biological functions, as well as efficacy and adverse reactions to oncological treatments, was used. Results: Data and blood samples were collected from 70 NSCLC patients. A bioinformatic analysis of all identified SNPs highlighted five clusters of patients based on variant aggregations and the associated genes, suggesting potential susceptibility to treatment-related toxicity. We assessed the feasibility of the platform and technically validated it by comparing NSCLC patients undergoing the same course of treatment with or without ADRs against the cluster combination. An odds ratio analysis confirmed the correlation between cluster allocation and increased ADR risk, indicating specific treatment susceptibilities. Conclusions: The ANTIBLASTIC DRUG MULTIPANEL PLATFORM was easily applicable and able to predict ADRs in NSCLC patients undergoing oncological treatments. The application of this novel predictive model could significantly reduce adverse drug reactions and improve the rate of chemotherapy completion, enhancing patient outcomes and quality of life. Its potential for broader prescription management suggests significant treatment improvements in cancer patients.

PMID:40149417 | DOI:10.3390/genes16030265

Cancers (Basel). 2025 Mar 17;17(6):1008. doi: 10.3390/cancers17061008.

ABSTRACT

Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.

PMID:40149342 | DOI:10.3390/cancers17061008

Cancers (Basel). 2025 Mar 7;17(6):913. doi: 10.3390/cancers17060913.

ABSTRACT

Pharmacogenomics, the study of how genetic variations influence drug response, has become integral to cancer treatment as personalized medicine evolves. This review aims to explore key pharmacogenomic biomarkers relevant to cancer therapy and their clinical implications, providing an updated and comprehensive perspective on how genetic variations impact drug metabolism, efficacy, and toxicity in oncology. Genetic heterogeneity among oncology patients significantly impacts drug efficacy and toxicity, emphasizing the importance of incorporating pharmacogenomic testing into clinical practice. Genes such as CYP2D6, DPYD, UGT1A1, TPMT, EGFR, KRAS, and BRCA1/2 play pivotal roles in influencing the metabolism, efficacy, and adverse effects of various chemotherapeutic agents, targeted therapies, and immunotherapies. For example, CYP2D6 polymorphisms affect tamoxifen metabolism in breast cancer, while DPYD variants can result in severe toxicities in patients receiving fluoropyrimidines. Mutations in EGFR and KRAS have significant implications for the use of targeted therapies in lung and colorectal cancers, respectively. Additionally, BRCA1/2 mutations predict the efficacy of PARP inhibitors in breast and ovarian cancer. Ongoing research in polygenic risk scores, liquid biopsies, gene-drug interaction networks, and immunogenomics promises to further refine pharmacogenomic applications, improving patient outcomes and reducing treatment-related adverse events. This review also discusses the challenges and future directions in pharmacogenomics, including the integration of computational models and CRISPR-based gene editing to better understand gene-drug interactions and resistance mechanisms. The clinical implementation of pharmacogenomics has the potential to optimize cancer treatment by tailoring therapies to an individual's genetic profile, ultimately enhancing therapeutic efficacy and minimizing toxicity.

PMID:40149251 | DOI:10.3390/cancers17060913

Sci Rep. 2025 Mar 27;15(1):10563. doi: 10.1038/s41598-024-83178-w.

ABSTRACT

Despite the abundance of large-scale molecular and drug-response data, current research on early-onset Parkinson's disease (EOPD) markers often lacks mechanistic interpretations of drug-gene relationships, limiting our understanding of how drugs exert their therapeutic effects. While existing studies provide valuable EOPD markers, the mechanisms by which targeted drugs act remain poorly understood. We propose DTI-Prox, a novel workflow that identifies potentially overlooked EOPD markers and suggests relevant drug targets. DTI-Prox employs network proximity to measure how closely connected a drug and gene are within a biological network. Additionally, node similarity, which assesses the functional resemblance between network nodes, reveals meaningful drug-gene connections. DTI-Prox identifies 417 novel drug-target pairs and four previously unreported EOPD markers (PTK2B, APOA1, A2M, and BDNF), demonstrating significant pathway enrichment in neurodegenerative processes. Notably, shared pathway analysis shows that prioritized drugs such as Amantadine, Apomorphine, Atropine, Benztropine, Biperiden, Bromocriptine, Cabergoline, Carbidopa, and Citalopram, currently used for other conditions, interact with key EOPD-associated diagnostic markers, suggesting their potential for drug repurposing. The constructed functional network's validity is reinforced by statistically significant drug-target pairs. The findings provide new insights into EOPD drug mechanisms and identify promising therapeutic candidates, potentially leading to more effective, personalized treatment approaches for EOPD patients.

PMID:40148390 | DOI:10.1038/s41598-024-83178-w

Int J Infect Dis. 2025 Mar 25:107895. doi: 10.1016/j.ijid.2025.107895. Online ahead of print.

ABSTRACT

BACKGROUND: NAT2 polymorphisms affect isoniazid metabolism, but their effect on mortality among individuals with tuberculosis (TB) remains unclear.

METHODS: This study used data from two TB cohorts (2005-2011, 2014-2020) and death certificate records in Thailand. Newly diagnosed Thai individuals treated with isoniazid-containing regimens were included. NAT2 genotypes-rapid, intermediate, and slow acetylator (RA, IA, SA)-were classified via haplotype inference. The primary outcome was 1-year all-cause mortality, while secondary outcomes included TB-related mortality, TB+respiratory disease-related mortality recorded in the vital registration system, and death as a TB treatment outcome. Adjusted hazard ratios (aHRs) relative to the IA type were estimated using stratified Cox proportional hazards models. Subgroup analyses targeted individuals with isoniazid-resistant TB and HIV infection.

RESULTS: A total of 1,065 individuals (766 males; mean age=51 years) were analyzed. Individuals with RA had a 1.70-fold greater all-cause mortality risk (95% CI: 1.03-2.80) than IA. The aHRs for RA were 1.14 (0.43-3.03) for TB-related mortality, 1.59 (0.80-3.18) for TB+respiratory disease-related mortality, and 1.26 (0.67-2.14) for TB treatment outcome death. Among individuals with isoniazid-resistant TB, those with RA had a 4.68-fold (1.14-19.12) greater aHR for all-cause mortality.

CONCLUSION: The RA type is associated with increased 1-year all-cause mortality.

PMID:40147587 | DOI:10.1016/j.ijid.2025.107895

Annu Rev Genomics Hum Genet. 2025 Mar 27. doi: 10.1146/annurev-genom-121323-104008. Online ahead of print.

ABSTRACT

Genetic variation is a major determinant of drug response across populations. Owing to advances in sequencing technologies over the last two decades, several clinically actionable variants or haplotypes have been characterized in genes that encode proteins mediating drug pharmacokinetics or pharmacodynamics. Therefore, clinical application of pharmacogenomics has gained significant traction as a promising tool for enabling drug therapy optimization to mitigate adverse drug reactions while promoting drug efficacy. However, the implementation of pharmacogenetics testing has been slow in African settings and other resource-limited global regions. Moreover, there is a need to address gaps in various pharmacogenomics knowledgebases, especially regarding the genetic diversity in underrepresented populations. It is also important to ensure that emerging assays and technologies do not heighten existing healthcare disparities affecting African populations. We present the status of pharmacogenomics in Africa, highlighting its potential to impact health outcomes in the safe and efficacious use of medicines.

PMID:40146997 | DOI:10.1146/annurev-genom-121323-104008

PLoS Med. 2025 Mar 27;22(3):e1004565. doi: 10.1371/journal.pmed.1004565. eCollection 2025 Mar.

ABSTRACT

BACKGROUND: Adverse drug reactions (ADRs) harm patients and are costly for healthcare systems. Genetic variation contributes to variability in medication response and prospective knowledge of these variants can decrease risk of ADRs, as shown in the PREPARE trial. Reduction in ADRs would affect only those reactions to drugs contained in well-validated pharmacogene-drug pairs. The scope of ADRs represented by these drugs on a population scale is unclear. The objective of this study was to characterize the pharmacogene-drug-associated ADR reporting landscape from a national regulatory pharmacovigilance dataset to elucidate the scale of potential ADR mitigation by pharmacogenomics (PGx) implementation.

METHODS AND FINDINGS: All publicly available Yellow Card ADR reports to the United Kingdom Medicines and Healthcare Products Regulatory Agency, from 1963 to 2024, were compiled using programmatic data extraction. The ADRs were analysed with descriptive statistics, stratified by PGx status and by associated genes. Prescribing prevalence from the literature was compared with age range matched ADR reports for PGx-associated drugs. There were 1,345,712 ADR reports, attributed to 2,499 different substances. 115,789 adverse drug reports (9%) were associated with drugs for which ADR risk can be modified based on pharmacogenomic prescribing guidance. Seventy-five percent of these (n = 87,339) were due to medicines which interact with only three pharmacokinetic pharmacogenes (CYP2C19, CYP2D6, SLCO1B1). Forty-seven percent of all the PGx mitigatable ADRs identified were attributed to psychiatric medications (n = 54,846), followed by 24% attributed to cardiovascular medications (n = 28,279). Those experiencing PGx mitigatable ADRs, as compared with non-PGx mitigatable ADRs, were older and the ADRs more often consisted of severe non-fatal reactions. Many PGx-associated psychiatric drug ADRs were overrepresented as compared with prescribing prevalence, but fatal cardiac arrhythmias were uncommon consequences, comprising only 0.4% of these ADRs (n = 172 of n = 48,315 total ADRs). Limitations of this data source include under reporting of ADRs and reporting bias. These findings are based on analysis of the Yellow Card dataset described and may not represent all ADRs from a generalised patient population.

CONCLUSIONS: Nine percent of all reported ADRs are associated with drugs where a genetic variant can cause heightened risk of an ADR and inform prescribing. A panel of only three pharmacogenes could potentially mitigate three in every four PGx modifiable ADRs. Based on our findings, Psychiatry may be the single highest impact specialty to pilot PGx to reduce ADRs and associated morbidity, mortality and costs.

PMID:40146782 | DOI:10.1371/journal.pmed.1004565

Clin Transl Sci. 2025 Apr;18(4):e70173. doi: 10.1111/cts.70173.

ABSTRACT

Lurbinectedin is an oncogenic transcription inhibitor indicated for the treatment of small cell lung cancer (SCLC), which has also shown activity against other malignancies. In this work, two independent cohorts of 180 (discovery cohort) and 719 (validation cohort) cancer patients receiving lurbinectedin in Phases I, II, or III clinical trials were enrolled. Using a population pharmacokinetic (popPK) model of the discovery cohort, patients with extremely high (n = 10, cohort 1) and low (n = 10, cohort 2) etaCL values (i.e., a variable used as a surrogate of unexplained CL interindividual variability) were identified. They were sequenced for 42 candidate genes involved in lurbinectedin pharmacokinetics. A total of 34 variants located in 20 genes were significantly associated with lurbinectedin etaCL; the best nine hits (located in CYP3A5, CYP3A4, ABCB1, ARNT, NR5A2, NR1H4, and FOXA3) were subsequently genotyped in the validation cohort. A strong additive association between CYP3A4 and CYP3A5 genotypes (informed as a CYP3A activity score [AS] variable) and lurbinectedin clearance (CL) and exposure was confirmed, for example, patients with an AS of 3, 2, or 1 showed a 2.3-, 1.6-, and 1.5-fold higher total lurbinectedin CL compared to those with an AS of 0 and 2.3-, 1.8-, and 1.6-fold higher unbound lurbinectedin CL. In conclusion, preemptive CYP3A genotyping may offer a valuable approach for personalizing treatment with lurbinectedin in cancer patients.

PMID:40146606 | DOI:10.1111/cts.70173

Curr Psychiatry Rep. 2025 Mar 27. doi: 10.1007/s11920-025-01606-8. Online ahead of print.

ABSTRACT

Bipolar Disorder (BD) is a chronic mental health condition characterized by significant mood swings, including periods of mania or hypomania and depression. Affecting approximately 1-2% of the global population, BD is associated with impaired social functioning, decreased quality of life, and an increased risk of suicide. The disorder presents a substantial burden on healthcare systems and imposes significant economic costs due to lost productivity and the need for extensive treatment and support services. This comprehensive review synthesizes global trends in BD pharmacotherapy over the past 1 to 3 years, focusing on emerging medications, novel treatment protocols, and ongoing debates within the field. Additionally, the review explores differences in prescribing patterns across developed and developing countries, introduces the impact of pharmacogenomics and personalized medicine on treatment outcomes. PURPOSE OF REVIEW: The primary purpose of this review is to provide a comprehensive and up-to-date synthesis of the global trends in the use of medications for the treatment of BD over the past 1 to 3 years. This review aims to outline the latest studies, clinical trials, and meta-analyses relevant to BD pharmacotherapy, highlighting new discoveries and advancements. Furthermore, this review will address ongoing debates and controversies in the field, such as the role of antidepressants in BD treatment and the long-term use of antipsychotics, aiming to bridge knowledge gaps and guide future research directions. RECENT FINDINGS: Studies continue to reinforce the efficacy of lithium in mood stabilization and reduction of suicidal behavior, despite its declining use due to safety concerns. Mood stabilizing anticonvulsants like valproate and carbamazepine continue to be vital alternatives, each with distinct side effect profiles necessitating careful patient monitoring. The approval and increasing use of novel atypical antipsychotics, such as lurasidone (2013) and cariprazine (2015), has expanded treatment options, offering efficacy in different phases of BD with relatively favorable side effect profiles. Antidepressants remain contentious, with evidence suggesting their benefits primarily when used in combination with mood stabilizers. Emerging agents like lumateperone (Dec 2021) and esketamine show promise, while pharmacogenomic research is paving the way for more personalized treatments. The landscape of BD pharmacotherapy is marked by significant advancements and ongoing challenges. Lithium and mood stabilizing anticonvulsants remain foundational treatments, albeit with adherence challenges and side effect concerns. The advent of new atypical antipsychotics and novel agents offers promising therapeutic options, while antidepressants continue to be debated. Personalized medicine and pharmacogenomics could emerge as transformative approaches, allowing for more tailored and effective treatments. However, disparities in medication accessibility between developed and developing countries highlight the need for global collaboration to optimize BD management. Continued research and innovation are essential to addressing the complexities of BD and improving patient outcomes worldwide.

PMID:40146356 | DOI:10.1007/s11920-025-01606-8

Clin Transl Sci. 2025 Apr;18(4):e70210. doi: 10.1111/cts.70210.

ABSTRACT

Monitoring whole blood tacrolimus concentrations is standard in clinical practice; however, it may not fully reflect its therapeutic effects, as tacrolimus primarily acts within lymphocytes. While various intracellular quantification methods have been developed, many involve complex procedures such as evaporation, reconstitution, or specialized tools (e.g., magnetic beads, online solid-phase extraction), limiting their accessibility. This study aimed to develop and validate a streamlined, sensitive method for measuring intracellular tacrolimus concentrations using 5×105 peripheral blood mononuclear cells (PBMCs). Tacrolimus concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PBMCs were aliquoted into 50 μL volumes containing 5×105 cells and prepared via acetonitrile-based protein precipitation. Chromatographic separation was performed using a Luna C18 column with a gradient mobile phase consisting of water with 20 mM ammonium acetate, 0.1% formic acid, and methanol at a flow rate of 0.4 mL/min. The method demonstrated excellent linearity between 0.1 and 25 ng/mL, corresponding to intracellular concentrations of 1-250 pg/5×105 cells (r2 = 0.999). Intra- and interday accuracy ranged from 98.1% to 109.8%, with precision between 2.08% and 8.70% across validation runs. Extraction recovery was high (93.0%-97.2%), with minimal matrix effects (100.9% at low QC and 111.6% at high QC). This validated LC-MS/MS method provides a rapid, reliable, and sensitive approach for pharmacokinetic studies and clinical applications, facilitating intracellular tacrolimus monitoring in transplant patients.

PMID:40145774 | DOI:10.1111/cts.70210

JHLT Open. 2024 Aug 6;6:100134. doi: 10.1016/j.jhlto.2024.100134. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Tacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk period.

METHODS: We conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group cohort. We used nonlinear mixed-effects regression to derive a population PK model in 270 patients and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and a multivariable model was developed using forward and backward stepwise selection. The performance of the final model in the validation cohort was examined with calculation of prediction error (PE).

RESULTS: We developed a 1-compartment base model with a fixed rate absorption constant. Covariates improving model fit were postoperative day, hematocrit, transplant type, CYP3A5 genotype, weight, and exposure to cytochrome p450 enzyme (CYP) inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than 3-fold over the 14-day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95% confidence interval 30.8%-41.9%) and a median PE of 7.2% (interquartile range -29.3% to 70.53%).

CONCLUSIONS: Tacrolimus clearance is highly dynamic during the early postlung transplant period. Population PK models that include lung-transplant-specific covariates may enable precision dosing algorithms that account for this highly dynamic clearance. Future multicenters studies including a broader set of covariates are warranted.

PMID:40145052 | PMC:PMC11935331 | DOI:10.1016/j.jhlto.2024.100134