Pharmacogenomics最新文献

Introduction: The cytochrome P450 2C19 (CYP2C19) enzyme plays a critical role in the metabolism of several clinically important drugs, but the genetic polymorphisms of CYP2C19 have been partially characterized in the Chinese population.

Methods: Genomic DNA from 1210 Chinese Han individuals was subjected to next-generation sequencing to screen for CYP2C19 variants, and newly identified mutations were confirmed by Sanger sequencing. CYP2C19 microsomes were expressed in vitro using an insect cell expression system, and their metabolic activity toward (S)-mephenytoin was quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).

Results: Genetic screening of CYP2C19 gene in 1210 Chinese Han individuals was performed and identified 11 previously unreported variants. Recombinant expression of these novel variants in insect microsomes demonstrated that approximately half of the variants exhibited protein expression levels comparable to the wild type. Using (S)-mephenytoin as a probe substrate, in vitro metabolic activity assays revealed that five variants (G79X, D188fs, A297D, A297V, and T302R) exhibited abolished enzymatic activity, whereas the remaining variants showed significantly reduced activity compared to the wild-type enzyme.

Conclusion: This study reveals a high prevalence of functionally impaired rare CYP2C19 variants in the Chinese Han population, underscoring their potential clinical relevance for personalized medicine.

Aims: Sequential Anthracycline-Taxane chemotherapy is standard treatment for BC. This study examines the combined impact of low BMI and CYP polymorphisms on treatment response.

Method: BMI was assessed before chemotherapy, and clinical response was evaluated using RECIST v.1. Four SNPs in CYP2C9, CYP2C19, and CYP3A4 gene were analyzed in 148 samples using PCR-RFLP.

Results: CYP2C19 (G681A) was significantly associated with treatment non-responsiveness in all genetic models namely dominant (OR11.119; 95%CI [5.103-24.228], p < 0.0001), recessive (15.818; [4.548-55.015]; p < 0.0001), codominant (χ² 48.229; p < 0.0001). No significant association was found in other two genes CYP2C9 (C430T, A32621C) and CYP3A4 (A392G). When combined with BMI, the CYP2C19 AA genotype showed significant associations with poor treatment response for low BMI group across all genetic models: dominant (9.60; [2.892-31.864]; p < 0.0001), recessive (1.473; [1.404-2.164]; p < 0.001), and codominant (χ² 18.897; p < 0.0001) and AA associated with lowest PFS: 38 months; HR >1. OS (39.79 months; p = 0.039) were lowered among GA genotype with increased HR (HR 3.78; p = 0.031).

Conclusion: AA genotype at G681A in low BMI patients showed the poorest chemotherapy response and lowest PFS (HR>1). CYP2C19 variants (AA) may serve as predictive markers for non-responsiveness towards AC-T chemotherapy in low BMI BC patients, highlighting the need for genetic counselling and nutritional support to improve treatment outcomes.

Introduction: Precision medicine is the future of healthcare, and pharmacists are well-positioned to play a key role in pharmacogenomics (PGx). Experiential learning offers valuable opportunities to gain hands-on experience in clinical PGx practices. This study aimed to explore experiential learning opportunities in PGx for pharmacy education.

Methods: Four PGx clinics in the United States of America, which provide PGx services, were observed to assess the potential for experiential learning. Qualitative data were collected through observations of PGx clinic consultations and semi-structured interviews with four pharmacists, one at each site. This approach provided insight into the practice-based learning opportunities in PGx clinics to explore experiential learning.

Results: Multiple experiential learning opportunities were identified, including activities to develop knowledge and skills; conduct research; collaborate with an interprofessional team; create patient education resources; provide patient and healthcare education; provide comprehensive care; develop evidence-based medicine skills, including the use of PGx resources; address ethical, legal, and social implications of PGx, and leadership.

Conclusion: Pharmacogenomics clinics offer valuable experiential learning opportunities for pharmacy education. Collaboration between healthcare and higher education institutions is essential to create these opportunities, ensuring the development of pharmacists who are prepared to meet future healthcare needs.

Introduction: Transient ischemic attack (TIA) or ischemic stroke (IS) patients may have recurrent stroke incidents, especially when carrying CYP2C19 Loss-of-Function (LoF) alleles and taking clopidogrel. Recent studies suggest using alternative antiplatelets, e.g., prasugrel, ticagrelor, in these patients. However, the aggregated risk of recurrent stroke or composite vascular events in CYP2C19 genotype-guided prasugrel/ticagrelor against clopidogrel therapy in such TIA/IS patients remained unexplored.

Methods: A database search was performed to retrieve relevant studies. RevMan software was used to calculate the risk ratio (RR), considering p < 0.05 statistically significant.

Result: Six studies (14,124 TIA/IS patients) were considered. TIA/IS patients carrying CYP2C19 LoF alleles on ticagrelor/prasugrel therapy were associated with a significant reduction in the risk of composite vascular events (RR 0.76, 95% CI 0.66-0.89; p = 0.0004) and recurrent stroke (RR 0.76, 95% CI 0.64-0.90; p = 0.002) compared to the clopidogrel therapy. However, the bleeding events did not differ significantly (RR 0.91, 95% CI 0.65-1.27; p = 0.58) between the treatment groups.

Conclusion: TIA/IS patients inheriting CYP2C19 LoF alleles taking ticagrelor/prasugrel may significantly optimize the overall clinical benefits compared to those who are taking clopidogrel by reducing composite vascular events and recurrent stroke without elevating the risk of bleeding events.

Aims: To screen and validate rare variants in the protoporphyrin IX (PPIX)-metabolizing pathway associated with anti-tuberculosis drug-induced hepatitis (AT-DIH).

Methods: A two-stage matched case-control study was conducted. Firstly, a 1:1 matching design (50 cases and 50 controls) was adopted to screen for rare variants using whole exome sequencing (WES). Secondly, a 1:4 matching design (132 cases and 528 controls) was employed to validate these rare variants via TaqMan genotyping. The association between these variants and AT-DIH risk was evaluated using odds ratios (ORs) with 95% confidence intervals (CIs), with the false discovery rate (FDR) applied for multiple comparison correction.

Results: The optimal sequence kernel association test (SKAT-O) and set-based tests identified 19 and 1 genes significantly associated with AT-DIH, respectively. The nuclear receptor coactivator 3 (NCOA3) gene was detected by both methods (SKAT-O: p = 0.002; set-based tests: p = 0.038), and seven algorithms identified four NCOA3 rare variants as deleterious. Further validation showed that the CC genotype of rs2230782 increased the risk of AT-DIH (OR = 15.074, 95%CI: 1.442-157.525, FDR p = 0.046), and this association remained significant in the two-stage combined analysis (3 cases and 1 control with CC genotype, OR = 14.832, 95%CI: 1.422-154.695, FDR p = 0.048).

Conclusions: NCOA3 rs2230782 is associated with AT-DIH in Chinese anti-tuberculosis patients.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis and limited effective treatments. Standard chemotherapy offers modest survival benefits, and actionable genetic alterations are rare. RET gene fusions occur in less than 1% of PDAC cases but present a potential target for therapy. We describe a case of a 62-year-old woman with metastatic PDAC who progressed on two lines of chemotherapy. A RET fusion (TPR - RET) was identified via liquid biopsy and confirmed on tissue biopsy. Treatment with the selective RET inhibitor selpercatinib led to rapid symptom improvement, normalization of tumor markers, and significant tumor regression. A partial radiographic response of approximately 60% was achieved, with manageable toxicity. This case highlights the importance of comprehensive molecular profiling, including noninvasive methods like liquid biopsy, in identifying rare but actionable mutations. Emerging evidence from clinical trials supports the efficacy of RET inhibitors in RET-altered PDAC. Broader integration of genomic testing in PDAC may uncover new therapeutic opportunities and improve patient outcomes.

Metoprolol, a β1-selective blocker, is widely used for treating cardiovascular and non-cardiovascular conditions. Its pharmacokinetics (PK) and pharmacodynamics (PD) vary significantly between individuals, in part due to CYP2D6 genetic polymorphisms. Co-administration of CYP2D6 inhibitors can lead to phenotype-genotype discordance, known as phenoconversion, resulting in clinically significant changes in metoprolol exposure and response. This review examines studies of the combined impact of CYP2D6 genotype and inhibitor use on metoprolol PK and PD. A literature search of PubMed, Embase, and Scopus identified 17 relevant clinical studies. Strong inhibitors such as paroxetine and fluoxetine increased metoprolol exposure by up to 8-fold and induced phenoconversion in extensive metabolizers. Moderate inhibitors, including mirabegron and amiodarone, increased metoprolol exposure by 2- to 3-fold, particularly in those with high baseline CYP2D6 activity. These inhibitors also reduced heart rate and blood pressure, mimicking the response seen in poor metabolizers. Weak inhibitors caused minimal PK changes without notable PD effects. Severe adverse drug reactions, including bradycardia and hypotension, occurred with strong inhibitors, especially in patients with cardiovascular disease and reduced CYP2D6 function. CYP2D6 phenoconversion is a clinically important but often overlooked contributor to metoprolol response variability. Incorporating phenoconversion into clinical practice can lead to more effective pharmacotherapy with metoprolol.

Introduction: Supportive care in oncology aims to prevent and manage cancer-related side effects. This study reviews supportive medications for gastrointestinal cancer patients, analyzes usage patterns, biomarker frequencies, and feasibility of dose adjustments.

Methodology: A 10-year retrospective study was performed at Parirenyatwa group of Hospitals, Radiotherapy & Oncology Center evaluating the supportive care medicines prescribed for all gastrointestinal cancer patients.

Results: A total of 607 patients were analyzed, 42% receiving cancer-specific treatment and 58% best supportive care. Patients who receive cancer-specific treatment, 200 participants (78%) received at least one supportive care medicine compared to 250 (71%) in the best supportive care group (OR 1.4; 95% CI 0.96-2; p = 0.08).Seventeen different supportive care medications were prescribed, seven (41%) of these have pharmacogenomic biomarkers testing recommendation. More patients in the cancer-treated group received medicines with actionable pharmacogenomic biomarkers than in the best supportive care group (56% versus 40%; OR 1.9; 95% CI 1.38-2.66; p = 0.0001). PGX guidelines were fully implemented for tramadol, codeine, omeprazole, and ondansetron; partially for ibuprofen and celecoxib; and unimplementable for amitriptyline.

Conclusion: There is an opportunity to improve supportive care in gastrointestinal cancer patients through pharmacogenomics though some specific medicines challenges to full implementations are due to limited registered medicines.