Search Results (230)

Background: Tamoxifen is widely used in the treatment of hormone receptor-positive breast cancer and has been shown to successfully reduce recurrence and mortality rates. Nonetheless, variability in patient response to tamoxifen treatment is observed with up to 40% of patients experiencing recurrence. Genetic polymorphisms in pharmacogenes encoding enzymes involved in tamoxifen metabolism have been linked to some of this observed interindividual variability. The pharmacogenetics of tamoxifen in populations of African descent remain understudied, creating difficulties in pinpointing the primary factors behind the observed variable response. To address this gap, this study aimed to investigate the role of genetic variation in tamoxifen treatment outcomes in a South African cohort. Methods: Participants included 166 Mixed and African Ancestry breast cancer patients who had received tamoxifen treatment. Genetic characterization was performed for 53 single nucleotide polymorphisms (SNPs) and two copy number variations across eight drug-metabolizing enzymes, including cytochrome P450s (CYP2D6, CYP3A4, CYP3A5, CYP2B6), UDP-glucuronosyltransferases (UGT1A4), and sulfotransferases (SULT1A1, SULT1E1, SULT2A1). The association between genotypes and disease-free survival (DFS) was evaluated using Cox proportional hazards regression models. Results: The CYP2B6*1/*6 or *4/*9 genotype showed a nominal association with improved DFS (p = 0.049), with a similar trend observed for UGT1A4 rs11888492. In contrast, SULT1E1 rs3775779 heterozygosity showed a nominal association with reduced DFS (p = 0.044). SULT1A1 SNPs (rs4149393, rs4149394, rs1042157) demonstrated trends toward reduced DFS. Conclusions: These exploratory findings highlight the need for more inclusive pharmacogenomic research and point to potential biomarkers for optimizing tamoxifen therapy in African populations. Full article

Tuberculosis (TB) remains a major public health challenge in Peru, where interindividual variability in treatment response and drug-induced hepatotoxicity may be influenced by host genetic background. This study aimed to characterize clinically relevant polymorphisms in NAT2, CYP2E1, and SLCO1B1 in a cohort of TB patients from Southern Peru, a genetically underrepresented Andean population. Thirty-five adults receiving first-line therapy (isoniazid and rifampicin) underwent targeted Sanger sequencing of key functional variants among these three genes. NAT2 acetylator phenotypes were predominantly intermediate (68.6%), followed by rapid (20%) and slow (11.4%) profiles, with high minor allele frequencies for rs1041983 and rs1801280. CYP2E1 functional promoter variants were infrequent, whereas SLCO1B1 exhibited notable allelic heterogeneity, suggesting potential variability in rifampicin transport. Comparative analysis with previously reported Peruvian data revealed regional differences in acetylator distribution, supporting population-specific pharmacogenomic stratification. Although clinical toxicity outcomes were not evaluated, the high prevalence of reduced acetylation genotypes suggests a substantial proportion of patients may benefit from genotype-informed isoniazid dosing strategies. These findings provide foundational data for implementing precision medicine approaches using affordable and targeted technologies in TB management within Andean populations and support the integration of pharmacogenomics into national TB control programs. Full article

Traditional one size fits all pharmacotherapy often yields suboptimal clinical outcomes, preventable adverse drug reactions (ADRs), and significant drug waste, imposing substantial economic and ecological burdens on healthcare systems. This review evaluates the transformative potential of pharmacogenomics (PGx) testing, particularly cytochrome P450 (CYP) gene variants, as a foundation for an ecosystem-centric accountability framework for green pharmacy and links human metabolic variability to specific environmental outcomes. Personalized CYP profiling is shown to minimize the environmental release of unused drugs and potentially ecotoxic metabolites into aquatic ecosystems, in contrast to standard uniform drug use approaches. The limitations of ethnicity-based dosing models, which rely on population genetic variation, are examined in the context of increasing global genetic admixture. It is argued that individual genetic profiling, conceptualized as a PGx-Green Passport, provides a reliable safety standard that accounts for individual differences, thereby enhancing efficiency and well-being in a globalized society. By integrating clinical data, including real-world evidence on hospital utilization, with sustainability frameworks, this review demonstrates that PGx-guided therapy is not only a tool for clinical efficiency but also a fundamental requirement for systematically achieving environmentally sustainable healthcare. Full article

When using traditional approaches, such as pharmacokinetics and pharmacodynamics, the entire cellular or molecular response to drugs in the body cannot be fully ascertained or established. The oral medication process involves pharmacokinetics, followed by oral microbiomics and then gut microbiomics and pharmacodynamics. Recently, there has been increasing interest in the role of genetics (pharmacogenetics and pharmacogenomics) in both humans and microbiomes, as well as omics alterations (e.g., epigenetic, transcriptomic, proteomic, and metabolomic alterations as a consequence of drug exposure), which can help to ascertain the cellular responses to medications. Both the efficacy and toxicity of a drug are influenced by these factors. To assess these at an individual level, an integrative Personalized Medicine Model may be needed to help with medication management. Two example application cases for SSRIs and statins demonstrate the clinical usefulness of such a model, which can guide clinicians during drug selection and dosing to reduce reliance on trial-and-error, thus potentially improving patient outcomes and safety. Integrating this framework into practical clinical workflows requires the capture, analysis, and translation of multi-omics data in order to realize decision support protocols and actionable drug recommendations. This review also discusses IT requirements and different stakeholder roles. Although the proposed model can guide the treatment of diseases at the individual patient level, further research is still needed before it can be implemented as part of drug development research, clinical care, and healthcare delivery systems. Full article

Background/Objectives: Macrophages polarized into M1 and M2 phenotypes differentially regulate immune and drug responses. Despite their distinct functional roles, differences in UDP-glucuronosyltransferase (UGT) expression and enzymatic activity between M1 and M2 macrophages remain poorly understood. This study aimed to characterize differential UGT expression in M1 and M2 macrophages and to elucidate how UGT-mediated prostaglandin E₂ (PGE₂) glucuronidation modulates macrophage inflammatory responses. Methods: THP-1 cells were chemically differentiated into macrophages (M0) and subsequently polarized into M1 and M2 phenotypes. UGT expression profiles were assessed using RT-PCR, quantitative RT-PCR (qRT-PCR), and Western blot. UGT activity was compared by quantifying glucuronide metabolites derived from UGT-specific substrates using LC-MS/MS, along with measurement of free PGE₂ and PGE₂-glucuronide by ELISA. Pro-inflammatory cytokine expression and secretion in M1 macrophages were quantified using qRT-PCR and ELISA. Results: Expression of UGT1A1, UGT1A4, UGT1A5, UGT1A9, and UGT2B7 were markedly higher in M1 compared with M2 macrophages at both the mRNA and protein levels. Enhanced UGT activity in M1 macrophages was reflected by increased formation of estradiol-3-glucuronide and naloxone-3-glucuronide (both p < 0.01) and was attenuated in a concentration-dependent manner by diclofenac. Furthermore, PGE₂ glucuronidation was more pronounced in M1 macrophages, and inhibition of UGTs with atazanavir reduced PGE₂-glucuronide formation and pro-inflammatory cytokine production, including IL-1β, IL-6, and TNF-α. Conclusion: UGT-mediated PGE₂ glucuronidation in M1 macrophages contributes to the regulation of pro-inflammatory cytokine production. Collectively, these findings support a role for UGTs as modulators of inflammatory signaling, with differential expression and activity between M1 and M2 macrophages. Full article

Background: Treating depression and anxiety in adolescents can be challenging due to interindividual variability in medication response. With current trial-and-error prescribing practices, adolescents may undergo multiple medication changes over months or years before an effective and tolerated drug and dose are identified. Pharmacogenomic (PGx) testing can identify interindividual differences in drug metabolism, and evidence supporting PGx-guided prescribing in adults with mental disorders is growing. However, its impact on pediatric psychotropic prescribing remains underexplored. Methods: This is a protocol for a parallel-arm, multicentre, randomized controlled trial. Canadian adolescents aged 12–17 years who are initiating or switching a selective serotonin reuptake inhibitor (SSRI) for depression and/or an anxiety disorder under physician care are eligible. A total of 452 participants will be randomized 1:1 to PGx-guided SSRI prescribing (experimental) or SSRI prescribing based on current practice guidelines (control). Participants, caregivers, prescribing clinicians, outcome assessors, and investigators will be blinded to treatment allocation. Dual primary outcomes are symptom remission at 12 weeks, measured with the Quick Inventory of Depressive Symptomatology–Adolescent (QIDS-A17-SR) and the Screen for Child Anxiety Related Disorders (SCARED). Secondary outcomes, assessed at 4, 8, and 12 weeks, include participant- and physician-rated changes in depressive and anxiety symptoms, role functioning, health-related quality of life, health care utilization, cost-effectiveness, side-effect burden, medication burden, and adherence. Multiple testing will be addressed using the Hochberg method, and a parallel gated analysis will account for non-actionable genotypes. Secondary analysis will estimate minimal clinically important differences for symptom and role-functioning change with PGx-guided therapy. Discussion: At the time of writing, 36 participants have consented and been randomized to an intervention. This trial will evaluate whether PGx-guided prescribing improves symptom remission in adolescents treated with SSRIs. If efficacious, results should be interpreted with existing pediatric pharmacokinetic, observational, and adult trial data to inform PGx use in managing pediatric anxiety and depressive disorders. Full article

Background: Pharmacogenetic markers associated with the need to switch patients from methotrexate (MTX) to biologic agents in moderate-to-severe psoriasis remain insufficiently studied. The pharmacokinetics of MTX depend on the individual characteristics of the patient, as well as on the function of specific transporters and enzymes involved in its absorption, distribution, metabolism, and elimination; therefore, polymorphisms in genes encoding these proteins may be considered pharmacogenetic predictors of MTX intolerance or insufficient efficacy. This study aimed to investigate genetic variants associated with MTX intolerance or insufficient efficacy leading to therapy switch. Methods: A total of 80 patients with moderate-to-severe psoriasis were included: 43 who required switching from MTX to biologics and 37 who continued MTX therapy. Twelve polymorphisms in transporter and metabolism-related genes (ABCB1 (rs1045642), MTHFR (rs1801133), ABCB1 (rs1128503), ABCC2 (rs3740066), ABCC2 (rs717620), ABCG2 (rs2231137), GSTP1 (rs1695), SLC19A1 (rs1051266), COL18A1 (rs9977268), SLCO1B1 (rs2306283), SLCO1B1 (rs4149056), and ABCB1 (rs2229109)) were analyzed using next-generation sequencing. Results: Significant differences in genotype frequencies were observed for SLC19A1 rs1051266 (p = 0.03) and COL18A1 rs9977268 (p = 0.02). Carriers of the T allele in both genes were more frequent among patients requiring biologic therapy, suggesting a possible association with MTX intolerance or reduced efficacy. Conclusions: The study revealed an association between polymorphisms in the SLC19A1 rs1051266 and COL18A1 rs9977268 genes and the need to switch from MTX to biologic therapy in patients with moderate-to-severe psoriasis. These findings suggest that carriers of the C allele in these genes may have an increased risk of methotrexate intolerance. Full article

Background/Objectives: Patient interest in pharmacogenomics (PGx) is growing, yet literacy remains low. This study aims to evaluate patient perspectives on pharmacist-led PGx services, assessing community perceptions of PGx pharmacists, their perceived role in care, literacy levels, and willingness to pay for services. Methods: A brief survey was distributed via social media to participants in southern Ohio, northern Kentucky, and southeastern Indiana. This survey included the Minnesota Assessment of Pharmacogenomic Literacy (MAPL), Likert-style questions to assess preferences, and willingness to pay questions with open fields. Upon completion, 152 responses were received. After data cleaning, 82 responses were analyzed. Results: While 66% of participants preferred their primary care provider to order testing, 45% preferred a PGx pharmacist over their primary care provider to explain their results and medication implications. Conclusions: After being educated on the role of a PGx pharmacist, respondents preferred a PGx pharmacist to explain their PGx testing results and any medication implications. Full article

Background: Major Depressive Disorder (MDD) is a leading global health concern, yet its pharmacological management is hampered by a «trial-and-error» approach, with a significant proportion of patients failing to achieve remission with initial therapy. This challenge stems from the disorder’s marked biological heterogeneity, which is poorly captured by current broad diagnostic categories. This literature review synthesizes the latest evidence across three complementary fields poised to revolutionize MDD treatment: pharmacogenetics testing (PGT), therapeutic drug monitoring (TDM), and artificial intelligence (AI). We hypothesize that integrating all three facilitates the transition from empirical prescribing to model-informed precision dosing (MIPD), enabling prediction of optimal antidepressant selection and dosage before the first dose is administered. The convergence of these technologies, supported by an interdisciplinary framework, has the potential to enhance current treatment strategies and contribute to more individualized psychiatric care. Conclusions: Antidepressant therapy for MDD may be further optimized through the combined use of TDM, PGT, and digital tools. However, the development of this field requires ongoing research and interdisciplinary work. Full article

Background: Dravet syndrome, a severe early-onset epileptic encephalopathy, is treated with multiple antiepileptic drugs such as clobazam (CLB) and stiripentol (STP), increasing the risk of drug–drug interactions (DDIs). Given the limited pediatric pharmacokinetic data, this study developed physiologically based pharmacokinetic (PBPK) models for CLB and STP to optimize dosing and assess DDI risk across pediatric age groups. Methods: We developed PBPK models for CLB, its active metabolite, N-desmethylclobazam (N-CLB), and STP in healthy adults and pediatric patients with Dravet syndrome aged two years and older. We evaluated the inhibitory effect of STP on CLB and N-CLB metabolism, accounting for CYP2C19 phenotypes. The model was extrapolated to predict drug exposure in pediatric patients under two years of age. Results: PBPK models for CLB, N-CLB, and STP successfully recapitulated observed pharmacokinetics in healthy adults and pediatric patients older than two years. Model verification against clinical DDI data showed that co-administration of STP with CLB resulted in a clinically insignificant increase in CLB exposure (C_min ratio = 1.77). In contrast, N-CLB exposure increased approximately 7-fold in CYP2C19 extensive metabolizers (C_min ratio ≈ 7) and slightly decreased in poor metabolizers (C_min ratio = 0.9), consistent with the CYP2C19-dependent metabolism of N-CLB. Extrapolation to pediatric patients under two years of age predicted CLB, N-CLB, and STP exposures that were comparable to older children and remained within their reported efficacy and safety margins, suggesting no major ontogeny-related effect on exposure. Conclusions: The PBPK model supports the safe extrapolation of CLB and STP co-administration to pediatric Dravet syndrome patients as young as six months. Full article

Background: Pharmacogenetics (PGx), which examines how genetic variations influence drug metabolism and response, offers promise in hospice care where patients commonly experience polypharmacy, complex symptoms, and limited life expectancy. This study assessed the utility of PGx results in guiding medication adjustments to improve symptom management at the end of life. Methods: A retrospective chart review was conducted on ten patients enrolled in a Precision Hospice Program who had PGx results for six key metabolic genes. A PGx-trained pharmacist reviewed Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline-based recommendations, which were discussed during interdisciplinary hospice team meetings. Results: Patients had a mean age of 85.7 years and were prescribed an average of 17.9 medications. Among the 27 prescriptions reviewed, actionable gene–drug interactions were identified, primarily involving antidepressants and analgesics. Three patients underwent medication changes based on PGx guidance, including switching from citalopram to bupropion and adding morphine to tramadol therapy, which improved symptom control. Conclusion: While not yet routinely implemented in hospice settings, this pilot study suggests PGx-guided prescribing can support personalized medication decisions and enhance emotional and physical comfort in end-of-life care when test results are available. Full article

Background: Solute carrier organic anion transporter family member 1B1 (SLCO1B1) mediates statin uptake into hepatocytes, the primary sites of cholesterol production. While the impact of SLCO1B1 variation on statin-associated muscle symptoms (SAMS) is well-documented, its role in LDL-C reduction remains understudied. This single-center, retrospective cohort study evaluated whether SLCO1B1 variation affects statin effectiveness in 213 adults. Methods: The SLCO1B1 variant rs4149056 (NM_006446.5:c.521T>C) was tested to categorize patients by their SLCO1B1 function: normal, decreased, or poor. The primary endpoint was percent change in LDL-C from baseline to follow-up (≥6 weeks post-statin initiation), with secondary endpoints of SAMS occurrence and statin adherence. Results: Overall, the average LDL-C decreased by 32% across all groups. No significant difference in LDL-C reduction was observed between SLCO1B1 phenotypes (p = 0.24). Conclusions: SLCO1B1 variation did not significantly affect LDL-C reduction, SAMS occurrence, or statin adherence. However, the retrospective design and limited adherence data in this study represent important limitations warranting prospective validation studies. Full article

Tamoxifen remains the standard treatment for hormone-sensitive breast cancer. However, significant interindividual variability in treatment response is observed. This variability may be partially explained by differences in the biotransformation of tamoxifen, a prodrug, into its active metabolites. To address this, we conducted a comprehensive literature search across several databases to examine current evidence on single-gene and multi-gene variations throughout the metabolic and transport pathways of tamoxifen and their impact on pharmacokinetics and clinical efficacy. We also explore the influence of drug–drug–gene interactions and review clinical strategies currently employed to manage treatment variability. Overall, growing evidence highlights the influence of pharmacogenetic variability, particularly CYP2D6 polymorphisms, on tamoxifen metabolism. Although its clinical use remains cautious and limited, a combined approach involving pharmacogenetic testing and therapeutic monitoring or phenotyping may help address treatment variability. Full article

Thrombosis remains a leading preventable cause of global morbidity and mortality, with conditions like venous thromboembolism and atrial fibrillation affecting millions worldwide. Traditional anticoagulants (heparins, vitamin K antagonists) require careful monitoring due to narrow therapeutic windows. Direct oral anticoagulants (DOACs) greatly improved convenience and reduced certain hemorrhagic complications (notably intracranial hemorrhage) compared to warfarin, but bleeding, drug–drug interactions, and unmet needs in special populations persist. This review highlights emerging strategies to decouple antithrombotic efficacy from bleeding risk. Novel agents targeting factor XI or XII (small molecules, antibodies, antisense oligonucleotides) have shown in early trials robust thromboembolism prevention with low bleeding. Advances in pharmacogenomics, biomarker-guided dosing, artificial intelligence risk prediction, and digital monitoring promise to personalize therapy. We discuss optimized approaches for high-risk subgroups (cancer-associated thrombosis, extremes of body weight, renal/hepatic dysfunction, pregnancy, perioperative care, and COVID-19) with citations to current evidence. Finally, we outline critical systems-level considerations, including drug accessibility, cost-effectiveness, and educational strategies, that are necessary to realize precision anticoagulation. Our synthesis is grounded in recent peer-reviewed literature and emphasizes innovations likely to improve safety and efficacy of thromboprophylaxis. Full article