Pub Date : 2024-05-22DOI: 10.1038/s41397-024-00336-z
Lorenzo Chidiac, Hady Yazbeck, Rami Mahfouz, Nathalie K. Zgheib
Pharmacogenomics (PGx) research and applications are of utmost relevance in Lebanon considering its population genetic diversity. Moreover, as a country with regional leadership in medicine and higher education, Lebanon holds a strong potential in contributing to PGx research and clinical implementation. In this manuscript, we first review and evaluate the available PGx research conducted in Lebanon, then describe the current status of PGx practice in Lebanon while reflecting on the local and regional challenges, and highlighting areas for action, and opportunities to move forward. We specifically expand on the status of PGx at the American University of Beirut Faculty of Medicine and Medical Center as a case study and guide for the further development of local and regional comprehensive PGx research, teaching, and clinical implementation programs. We also delve into the status of PGx knowledge and education, and prospects for further advancement such as with online courses and certificates.
{"title":"Pharmacogenomics in Lebanon: current status, challenges and opportunities","authors":"Lorenzo Chidiac, Hady Yazbeck, Rami Mahfouz, Nathalie K. Zgheib","doi":"10.1038/s41397-024-00336-z","DOIUrl":"10.1038/s41397-024-00336-z","url":null,"abstract":"Pharmacogenomics (PGx) research and applications are of utmost relevance in Lebanon considering its population genetic diversity. Moreover, as a country with regional leadership in medicine and higher education, Lebanon holds a strong potential in contributing to PGx research and clinical implementation. In this manuscript, we first review and evaluate the available PGx research conducted in Lebanon, then describe the current status of PGx practice in Lebanon while reflecting on the local and regional challenges, and highlighting areas for action, and opportunities to move forward. We specifically expand on the status of PGx at the American University of Beirut Faculty of Medicine and Medical Center as a case study and guide for the further development of local and regional comprehensive PGx research, teaching, and clinical implementation programs. We also delve into the status of PGx knowledge and education, and prospects for further advancement such as with online courses and certificates.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-7"},"PeriodicalIF":2.8,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.1038/s41397-024-00335-0
Luka Penezić, Sandra Nađ-Škegro, Ayla Hadžavdić, Lana Ganoci, Željko Kaštelan, Vladimir Trkulja, Nada Božina
Variant allele at the inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C has been associated with increased enzyme activity and reduced susceptibility to mycophenolic acid (MPA) in vitro. It has been suggested associated with an increased risk of acute rejection in renal transplant recipients on MPA-based immunosuppression, but not unambiguously. We assessed one-year evolution of the estimated glomerular filtration rate (eGFR) in transplanted variant allele carriers and wild-type subjects, while controlling for a number of demographic, pharmacogenetic, (co)morbidity, and treatment baseline and time-varying covariates. The eGFR slopes to day 28 (GMR = 1.01, 95% CI 0.93–1.09), and between days 28 and 365 (GMR = 1.01, 95% CI 0.99–1.02) were practically identical in 52 variant carriers and 202 wild-type controls. The estimates (95%CIs) remained within the limits of ±20% difference even after adjustment for a strong hypothetical effect of unmeasured confounders. Polymorphism IMPDH2 3757T>C does not affect the renal graft function over the 1st year after transplantation.
单磷酸肌苷脱氢酶 2 型多态性 IMPDH2 3757T>C 的变异等位基因与体外酶活性增加和对霉酚酸（MPA）的敏感性降低有关。有研究表明，在使用基于 MPA 的免疫抑制剂的肾移植受者中，该基因与急性排斥反应风险增加有关，但并不明确。我们评估了移植变异等位基因携带者和野生型受试者一年的估计肾小球滤过率（eGFR）的变化情况，同时控制了一些人口统计学、药物遗传学、（并发）发病率、治疗基线和时变协变量。在52名变异基因携带者和202名野生型对照组中，到第28天的eGFR斜率（GMR = 1.01，95% CI 0.93-1.09）以及第28天和365天之间的eGFR斜率（GMR = 1.01，95% CI 0.99-1.02）几乎相同。即使在调整了未测量混杂因素的强烈假定影响后，估计值（95%CIs）仍在±20%的差异范围内。IMPDH2 3757T>C 多态性不会影响移植后第一年的肾移植功能。
{"title":"Inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C (rs11706052) and 12-month evolution of the graft function in renal transplant recipients on mycophenolate-based immunosuppression","authors":"Luka Penezić, Sandra Nađ-Škegro, Ayla Hadžavdić, Lana Ganoci, Željko Kaštelan, Vladimir Trkulja, Nada Božina","doi":"10.1038/s41397-024-00335-0","DOIUrl":"10.1038/s41397-024-00335-0","url":null,"abstract":"Variant allele at the inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C has been associated with increased enzyme activity and reduced susceptibility to mycophenolic acid (MPA) in vitro. It has been suggested associated with an increased risk of acute rejection in renal transplant recipients on MPA-based immunosuppression, but not unambiguously. We assessed one-year evolution of the estimated glomerular filtration rate (eGFR) in transplanted variant allele carriers and wild-type subjects, while controlling for a number of demographic, pharmacogenetic, (co)morbidity, and treatment baseline and time-varying covariates. The eGFR slopes to day 28 (GMR = 1.01, 95% CI 0.93–1.09), and between days 28 and 365 (GMR = 1.01, 95% CI 0.99–1.02) were practically identical in 52 variant carriers and 202 wild-type controls. The estimates (95%CIs) remained within the limits of ±20% difference even after adjustment for a strong hypothetical effect of unmeasured confounders. Polymorphism IMPDH2 3757T>C does not affect the renal graft function over the 1st year after transplantation.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-9"},"PeriodicalIF":2.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141072355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-15DOI: 10.1038/s41397-024-00334-1
Kimberly M. Deininger, Heather D. Anderson, George P. Patrinos, Christina Mitropoulou, Christina L. Aquilante
The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.
{"title":"Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data","authors":"Kimberly M. Deininger, Heather D. Anderson, George P. Patrinos, Christina Mitropoulou, Christina L. Aquilante","doi":"10.1038/s41397-024-00334-1","DOIUrl":"10.1038/s41397-024-00334-1","url":null,"abstract":"The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-11"},"PeriodicalIF":2.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41397-024-00334-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-18DOI: 10.1038/s41397-024-00332-3
Jianchang Qian, Tao Xu, Peipei Pan, Wei Sun, Guoxin Hu, Jianping Cai
To investigate the pharmacokinetic and pharmacodynamic profiles of volunteers carrying CYP2D6 genotypes with unknow metabolic phenotypes, a total of 22 volunteers were recruited based on the sequencing results. Peripheral blood and urine samples were collected at specific time points after oral administration of metoprolol. A validated high-performance liquid chromatography (HPLC) method was used to determine the concentrations of metoprolol and α-hydroxymetoprolol. Blood pressure and electrocardiogram were also monitored. The results showed that the main pharmacokinetic parameters of metoprolol in CYP2D6*1/*34 carriers are similar to those in CYP2D6*1/*1 carriers. However, in individuals carrying the CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 genotypes, the area under the curve (AUC) and half-life (t1/2) of metoprolol increased by 2-3 times compared to wild type. The urinary metabolic ratio of metoprolol in these genotypes is consistent with the trends observed in plasma samples. Therefore, CYP2D6*1/*34 can be considered as normal metabolizers, while CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 are intermediate metabolizers. Although the blood concentration of metoprolol has been found to correlate with CYP2D6 genotype, its blood pressure-lowering effect reaches maximum effectiveness at a reduction of 25 mmHg. Furthermore, P-Q interval prolongation and heart rate reduction are not positively correlated with metoprolol blood exposure. Based on the pharmacokinetic-pharmacodynamic model, this study clarified the properties of metoprolol in subjects with novel CYP2D6 genotypes and provided important fundamental data for the translational medicine of this substrate drug.
{"title":"Study on genotype and phenotype of novel CYP2D6 variants using pharmacokinetic and pharmacodynamic models with metoprolol as a substrate drug","authors":"Jianchang Qian, Tao Xu, Peipei Pan, Wei Sun, Guoxin Hu, Jianping Cai","doi":"10.1038/s41397-024-00332-3","DOIUrl":"10.1038/s41397-024-00332-3","url":null,"abstract":"To investigate the pharmacokinetic and pharmacodynamic profiles of volunteers carrying CYP2D6 genotypes with unknow metabolic phenotypes, a total of 22 volunteers were recruited based on the sequencing results. Peripheral blood and urine samples were collected at specific time points after oral administration of metoprolol. A validated high-performance liquid chromatography (HPLC) method was used to determine the concentrations of metoprolol and α-hydroxymetoprolol. Blood pressure and electrocardiogram were also monitored. The results showed that the main pharmacokinetic parameters of metoprolol in CYP2D6*1/*34 carriers are similar to those in CYP2D6*1/*1 carriers. However, in individuals carrying the CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 genotypes, the area under the curve (AUC) and half-life (t1/2) of metoprolol increased by 2-3 times compared to wild type. The urinary metabolic ratio of metoprolol in these genotypes is consistent with the trends observed in plasma samples. Therefore, CYP2D6*1/*34 can be considered as normal metabolizers, while CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 are intermediate metabolizers. Although the blood concentration of metoprolol has been found to correlate with CYP2D6 genotype, its blood pressure-lowering effect reaches maximum effectiveness at a reduction of 25 mmHg. Furthermore, P-Q interval prolongation and heart rate reduction are not positively correlated with metoprolol blood exposure. Based on the pharmacokinetic-pharmacodynamic model, this study clarified the properties of metoprolol in subjects with novel CYP2D6 genotypes and provided important fundamental data for the translational medicine of this substrate drug.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-7"},"PeriodicalIF":2.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140623317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-17DOI: 10.1038/s41397-024-00333-2
Deniz Türkmen, Jack Bowden, Jane A. H. Masoli, João Delgado, Chia-Ling Kuo, David Melzer, Luke C. Pilling
Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10−5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.
{"title":"Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone","authors":"Deniz Türkmen, Jack Bowden, Jane A. H. Masoli, João Delgado, Chia-Ling Kuo, David Melzer, Luke C. Pilling","doi":"10.1038/s41397-024-00333-2","DOIUrl":"10.1038/s41397-024-00333-2","url":null,"abstract":"Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10−5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-7"},"PeriodicalIF":2.8,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41397-024-00333-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.1038/s41397-024-00331-4
Yi-Chieh Chen, Han Wang, Jayawant N. Mandrekar, Carrie E. Robertson, Amaal J. Starling, Fred M. Cutrer, Chia-Chun Chiang
To investigate factors affecting the efficacy and tolerability of verapamil for migraine prevention using individual pharmacogenomic phenotypes. Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual. 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. 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. We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.
{"title":"Pharmacogenomic study—A pilot study of the effect of pharmacogenomic phenotypes on the adequate dosing of verapamil for migraine prevention","authors":"Yi-Chieh Chen, Han Wang, Jayawant N. Mandrekar, Carrie E. Robertson, Amaal J. Starling, Fred M. Cutrer, Chia-Chun Chiang","doi":"10.1038/s41397-024-00331-4","DOIUrl":"10.1038/s41397-024-00331-4","url":null,"abstract":"To investigate factors affecting the efficacy and tolerability of verapamil for migraine prevention using individual pharmacogenomic phenotypes. Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual. 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. 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. We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-7"},"PeriodicalIF":2.8,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140582105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-18DOI: 10.1038/s41397-024-00330-5
Vasileios Fragoulakis, Margarita-Ioanna Koufaki, Candace Joefield-Roka, Gere Sunder-Plassmann, Christina Mitropoulou
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.
{"title":"Cost-utility analysis of pharmacogenomics-guided tacrolimus treatment in Austrian kidney transplant recipients participating in the U-PGx PREPARE study","authors":"Vasileios Fragoulakis, Margarita-Ioanna Koufaki, Candace Joefield-Roka, Gere Sunder-Plassmann, Christina Mitropoulou","doi":"10.1038/s41397-024-00330-5","DOIUrl":"10.1038/s41397-024-00330-5","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 2","pages":"1-7"},"PeriodicalIF":2.8,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41397-024-00330-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140149677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1038/s41397-024-00326-1
Santenna Chenchula, Shubham Atal, Chakradhara Rao S Uppugunduri
Adverse drug reactions (ADRs) are a significant public health concern and a leading cause of hospitalization; they are estimated to be the fourth leading cause of death and increasing healthcare costs worldwide. Carrying a genetic variant could alter the efficacy and increase the risk of ADRs associated with a drug in a target population for commonly prescribed drugs. The use of pre-emptive pharmacogenetic/omic (PGx) testing can improve drug therapeutic efficacy, safety, and compliance by guiding the selection of drugs and/or dosages. In the present narrative review, we examined the current evidence of pre-emptive PGx testing-based treatment for the prevention of ADRs incidence and hospitalization or emergency department visits due to serious ADRs, thus improving patient safety. We then shared our perspective on the importance of preemptive PGx testing in clinical practice for the safe use of medicines and decreasing healthcare costs.
{"title":"A review of real-world evidence on preemptive pharmacogenomic testing for preventing adverse drug reactions: a reality for future health care","authors":"Santenna Chenchula, Shubham Atal, Chakradhara Rao S Uppugunduri","doi":"10.1038/s41397-024-00326-1","DOIUrl":"10.1038/s41397-024-00326-1","url":null,"abstract":"Adverse drug reactions (ADRs) are a significant public health concern and a leading cause of hospitalization; they are estimated to be the fourth leading cause of death and increasing healthcare costs worldwide. Carrying a genetic variant could alter the efficacy and increase the risk of ADRs associated with a drug in a target population for commonly prescribed drugs. The use of pre-emptive pharmacogenetic/omic (PGx) testing can improve drug therapeutic efficacy, safety, and compliance by guiding the selection of drugs and/or dosages. In the present narrative review, we examined the current evidence of pre-emptive PGx testing-based treatment for the prevention of ADRs incidence and hospitalization or emergency department visits due to serious ADRs, thus improving patient safety. We then shared our perspective on the importance of preemptive PGx testing in clinical practice for the safe use of medicines and decreasing healthcare costs.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 2","pages":"1-6"},"PeriodicalIF":2.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10942860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140141108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-14DOI: 10.1038/s41397-024-00327-0
Tianbo Jin, Xiaoli Liu, Yuhe Wang, Yijin Qi, Xuemei Li, Li Wang, Xue He
Tibetan medicine Gaoyuan’an capsule (GYAC) is widely used to prevent pulmonary edema at high altitude, but the specific mechanism has not been explored. In this study, we analyzed the mechanism of GYAC in hypoxia tolerance, and provided a new idea for the prevention and treatment of altitude disease. The effective components and corresponding targets of GYAC were screened out by the Chinese herbal medicine network database, and the key targets of hypoxia tolerance were retrieved by Genecards, OMIM and PubMed database. Cytoscape 3.7.2 was used to construct GYAC ingredient-target-hypoxia tolerance-related target network. GO function annotation and KEGG enrichment analysis were performed to predict the pathways in which target genes may be involved, and molecular docking was used to verify the binding ability of the compound to target genes. In vitro, the above results were further verified by molecular experiment. We found that GYAC can improve hypoxia tolerance by regulating various target genes, including IL6, IFNG, etc. The main regulatory pathways were HIF-1 signaling pathway. Molecular docking showed that the affinity between luteolin and target genes (IL6, IFNG) were better. In vitro, we observed that hypoxia can inhibit cell viability and promote apoptosis of H9C2 cell. And hypoxia can promote the expression of LDH. After the addition of luteolin, the decrease of cell viability, the increase of cell apoptosis, LDH release and the decrease of mitochondrial membrane potential were inhibited. Besides, inflammatory related factors (IL-6, IL-10, IL-2, IFNG and VEGFA) expression were also inhibited hypoxic cell models. The results of network pharmacology and molecular docking showed that luteolin, a monomeric component of GYAC, played a role in hypoxia tolerance through a variety of target genes, such as IL6, IFNG. What’s more, we have discovered that luteolin can reduce the inflammatory response in cardiac myocytes, thereby alleviating mitochondrial damage, and ultimately enhancing the hypoxia tolerance of H9C2 cardiomyocytes.
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Pub Date : 2024-03-05DOI: 10.1038/s41397-024-00329-y
Benjamin Cross, Richard M. Turner, J. Eunice Zhang, Munir Pirmohamed
Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups.
抗凝剂是广泛应用于内科和外科的强效治疗药物，用于抗凝的费用也在不断增加。虽然华法林仍是广泛使用的口服抗凝药，但直接口服抗凝药（DOAC）的处方量也在迅速增加。以肝素为基础的肠外抗凝剂包括非分数肝素和低分子量肝素（LMWHs）。在临床实践中，抗凝剂的耐受性一般都很好，但个体间的反应差异明显。抗凝剂反应的这种变异性可导致严重的血栓形成、出血和非目标不良反应，如肝素诱导的血小板减少症（HIT）。本综述旨在强调与抗凝剂反应变异相关的遗传、环境和临床因素，并审查当前的证据基础，以便根据已确定的患者亚群调整药物、剂量和/或监测决策，从而提高抗凝剂的安全性。此外，还确定了可从进一步研究中获益的领域。VKORC1、CYP2C9 和 CYP4F2 中已验证的变异构成了不同华法林反应的生物标志物，而根据基因型确定华法林剂量已被证明可减少不良临床事件的发生。CES1 的多态性似乎与达比加群的暴露有关，但侧重于出血等临床结果的基因研究却很少。体重对 LMWH 反应的影响以及抗 Xa 水平与临床结果之间的关系值得进一步关注。归根结底，安全有效的抗凝治疗需要对导致不同反应的因素进行更深入的解析，还需要进一步的前瞻性研究来确定已识别的高风险亚组的最佳治疗策略。
{"title":"Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?","authors":"Benjamin Cross, Richard M. Turner, J. Eunice Zhang, Munir Pirmohamed","doi":"10.1038/s41397-024-00329-y","DOIUrl":"10.1038/s41397-024-00329-y","url":null,"abstract":"Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 2","pages":"1-23"},"PeriodicalIF":2.8,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41397-024-00329-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140035375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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