Pub Date : 2024-06-18DOI: 10.1038/s41397-024-00340-3
Adriana Vázquez-Medina, Marion T. Turnbull, Courtney L. James, Jennifer B. Cowart, Elizabeth Lesser, Rickey E. Carter, Owen A. Ross, David A. Miller, James F. Meschia, Aixa De Jesús Espinosa, Richard Weinshilboum, W. David Freeman
Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.
{"title":"Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics","authors":"Adriana Vázquez-Medina, Marion T. Turnbull, Courtney L. James, Jennifer B. Cowart, Elizabeth Lesser, Rickey E. Carter, Owen A. Ross, David A. Miller, James F. Meschia, Aixa De Jesús Espinosa, Richard Weinshilboum, W. David Freeman","doi":"10.1038/s41397-024-00340-3","DOIUrl":"10.1038/s41397-024-00340-3","url":null,"abstract":"Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 4","pages":"1-7"},"PeriodicalIF":2.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421898","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 : 2024-06-01DOI: 10.1038/s41397-024-00339-w
Daniel T. Barratt, Pål Klepstad, Ola Dale, Stein Kaasa, Andrew A. Somogyi
The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7–2.3) versus 1.0 (0.5–1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20–81) versus 29 (14–60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22–0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02–0.63)) and IL6R rs8192284 carrier (0.55 (0.34–0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2–9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.
{"title":"Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects","authors":"Daniel T. Barratt, Pål Klepstad, Ola Dale, Stein Kaasa, Andrew A. Somogyi","doi":"10.1038/s41397-024-00339-w","DOIUrl":"10.1038/s41397-024-00339-w","url":null,"abstract":"The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7–2.3) versus 1.0 (0.5–1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20–81) versus 29 (14–60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22–0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02–0.63)) and IL6R rs8192284 carrier (0.55 (0.34–0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2–9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-8"},"PeriodicalIF":2.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11144121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141187105","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 : 2024-05-27DOI: 10.1038/s41397-024-00338-x
Yitian Zhou, Sebastian Pirmann, Volker M. Lauschke
Lack of efficacy or adverse drug response are common phenomena in pharmacological therapy causing considerable morbidity and mortality. It is estimated that 20–30% of this variability in drug response stems from variations in genes encoding drug targets or factors involved in drug disposition. Leveraging such pharmacogenomic information for the preemptive identification of patients who would benefit from dose adjustments or alternative medications thus constitutes an important frontier of precision medicine. Computational methods can be used to predict the functional effects of variant of unknown significance. However, their performance on pharmacogenomic variant data has been lackluster. To overcome this limitation, we previously developed an ensemble classifier, termed APF, specifically designed for pharmacogenomic variant prediction. Here, we aimed to further improve predictions by leveraging recent key advances in the prediction of protein folding based on deep neural networks. Benchmarking of 28 variant effect predictors on 530 pharmacogenetic missense variants revealed that structural predictions using AlphaMissense were most specific, whereas APF exhibited the most balanced performance. We then developed a new tool, APF2, by optimizing algorithm parametrization of the top performing algorithms for pharmacogenomic variations and aggregating their predictions into a unified ensemble score. Importantly, APF2 provides quantitative variant effect estimates that correlate well with experimental results (R2 = 0.91, p = 0.003) and predicts the functional impact of pharmacogenomic variants with higher accuracy than previous methods, particularly for clinically relevant variations with actionable pharmacogenomic guidelines. We furthermore demonstrate better performance (92% accuracy) on an independent test set of 146 variants across 61 pharmacogenes not used for model training or validation. Application of APF2 to population-scale sequencing data from over 800,000 individuals revealed drastic ethnogeographic differences with important implications for pharmacotherapy. We thus think that APF2 holds the potential to improve the translation of genetic information into pharmacogenetic recommendations, thereby facilitating the use of Next-Generation Sequencing data for stratified medicine.
{"title":"APF2: an improved ensemble method for pharmacogenomic variant effect prediction","authors":"Yitian Zhou, Sebastian Pirmann, Volker M. Lauschke","doi":"10.1038/s41397-024-00338-x","DOIUrl":"10.1038/s41397-024-00338-x","url":null,"abstract":"Lack of efficacy or adverse drug response are common phenomena in pharmacological therapy causing considerable morbidity and mortality. It is estimated that 20–30% of this variability in drug response stems from variations in genes encoding drug targets or factors involved in drug disposition. Leveraging such pharmacogenomic information for the preemptive identification of patients who would benefit from dose adjustments or alternative medications thus constitutes an important frontier of precision medicine. Computational methods can be used to predict the functional effects of variant of unknown significance. However, their performance on pharmacogenomic variant data has been lackluster. To overcome this limitation, we previously developed an ensemble classifier, termed APF, specifically designed for pharmacogenomic variant prediction. Here, we aimed to further improve predictions by leveraging recent key advances in the prediction of protein folding based on deep neural networks. Benchmarking of 28 variant effect predictors on 530 pharmacogenetic missense variants revealed that structural predictions using AlphaMissense were most specific, whereas APF exhibited the most balanced performance. We then developed a new tool, APF2, by optimizing algorithm parametrization of the top performing algorithms for pharmacogenomic variations and aggregating their predictions into a unified ensemble score. Importantly, APF2 provides quantitative variant effect estimates that correlate well with experimental results (R2 = 0.91, p = 0.003) and predicts the functional impact of pharmacogenomic variants with higher accuracy than previous methods, particularly for clinically relevant variations with actionable pharmacogenomic guidelines. We furthermore demonstrate better performance (92% accuracy) on an independent test set of 146 variants across 61 pharmacogenes not used for model training or validation. Application of APF2 to population-scale sequencing data from over 800,000 individuals revealed drastic ethnogeographic differences with important implications for pharmacotherapy. We thus think that APF2 holds the potential to improve the translation of genetic information into pharmacogenetic recommendations, thereby facilitating the use of Next-Generation Sequencing data for stratified medicine.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-11"},"PeriodicalIF":2.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11129946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159216","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 : 2024-05-22DOI: 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}
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