Clinical Pharmacology & Therapeutics最新文献

{"title":"Exposure-Response Relationships for Axatilimab in Patients with Chronic Graft-Versus-Host Disease.","authors":"Yan-Ou Yang, Alina Volkova, Victor Sokolov, Xing Liu, Cristina Leon, Yuri Kosinsky, Jennifer Sheng, Xuejun Chen","doi":"10.1002/cpt.3731","DOIUrl":"https://doi.org/10.1002/cpt.3731","url":null,"abstract":"<p><p>Axatilimab, a high-affinity humanized monoclonal antibody that targets colony-stimulating factor 1 receptor, is approved for the treatment of chronic graft-versus-host disease (cGVHD). Here, we describe the exposure-response relationships for efficacy and safety in patients with cGVHD who received axatilimab. Exposure-efficacy relationships were assessed in treated patients in the AGAVE-201 study (n = 239); exposure-safety relationships were assessed in treated patients in AGAVE-201 (n = 239) and the phase 1/2 SNDX-6352-0503 study (n = 39). For binary or time-to-event endpoints, logistic or Cox regression analyses, respectively, were performed using axatilimab exposure metrics that were derived from a previously developed population pharmacokinetic/pharmacodynamic model. Overall response and ≥ 7-point improvement in modified Lee Symptom Scale responses were associated with axatilimab exposure, with lower axatilimab exposure increasing the odds of a response. Duration of response was not associated with axatilimab exposure. Ten of 11 safety endpoints were associated with axatilimab exposure, with higher axatilimab exposure increasing the odds of adverse events. Among the 3 regimens evaluated in AGAVE-201, the 0.3 mg/kg once every 2 weeks (Q2W) regimen had the highest predicted probability of response. Additionally, this dose group had the lowest predicted probability of event occurrence across all 10 safety endpoints associated with exposure among the evaluated regimens. Despite body weight influencing axatilimab exposure by > 20%, its effect on efficacy and safety endpoints remained minimal, with a maximum difference of ≤ 0.4% and ≤ 4.4% between the 1st and 4th quartiles of body weight, respectively. Taken together, these findings support the benefit-risk profile of axatilimab 0.3 mg/kg Q2W in patients with cGVHD.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic/Toxicodynamic Model for Polymyxin B in Critically Ill Patients to Identify the Risk of Nephrotoxicity.","authors":"Patrick O Hanafin, Ramya Mahadevan, Gauri G Rao, Alexandre P Zavascki, Ana Maria Sandri, Andrea Kwa, Marc H Scheetz, Christine J Kubin, Jayesh Shah, Benjamin P Z Cherng, Michael T Yin, Jiping Wang, Lu Wang, David P Calfee, Maureen Bolon, Anthony W Purcell, Roger L Nation, Jason M Pogue, Jian Li, Keith S Kaye","doi":"10.1002/cpt.3729","DOIUrl":"https://doi.org/10.1002/cpt.3729","url":null,"abstract":"<p><p>Polymyxins are used against highly resistant Gram-negative pathogens, and nephrotoxicity (acute kidney injury, AKI) is the major dose-limiting adverse effect. We aimed to develop a well-informed population pharmacokinetic/toxicodynamic (PK/TD) model using the largest polymyxin B-treated critically ill patient population studied to inform polymyxin B dosing strategies. Critically ill patients receiving intravenous polymyxin B for at least 48 hours were enrolled in an observational study. Serum creatinine (SCr) concentrations were collected from electronic medical records. PK/TD analysis and Monte Carlo simulations were performed to determine the probability of AKI, P(AKI), for clinically relevant treatments. Patients (N = 117) aged 18-94 received intravenous polymyxin B (1.33-6.00 mg/kg/day) for 1-50 days. The changes in SCr were described using an indirect response model. The effects of polymyxin B-induced functional kidney injury were characterized using 9 transit compartments (mean time to onset ~7 days), leading to a reduction in SCr elimination. Sex was identified as a significant covariate for baseline SCr₀. Concomitant amikacin or vancomycin use resulted in increased sensitivity to polymyxin B. On day 21, Low (fAUC_0-24,_SS = ~10 mg·h/L), medium (fAUC_0-24,SS = ~20 mg·h/L ), and high (fAUC_0-24,SS = ~40 mg·h/L) drug exposures resulted in a P(AKI) (> 1-fold SCr increase) of 25.8%, 32.5%, and 40.4%, respectively. This study, the largest to date, suggests that regimens ranging from low to high polymyxin B exposures can minimize P(AKI) over a longer duration (14 days). However, supratherapeutic exposure can be administered relatively safely when limited to a shorter duration (≤ 4 days). The population PK/TD model may be used to improve polymyxin B dosing to help conserve this last-line agent.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comedications Associated with Immune-Related Adverse Events from Immune-Checkpoint Inhibitors.","authors":"Léonard Laurent, Baptiste Abbar, Kevin Bihan, Elise Dumas, Floriane Jochum, Bénédicte Lebrun-Vignes, Jean-Philippe Spano, Joe-Elie Salem, Anne-Sophie Hamy, Fabien Reyal, Paul Gougis","doi":"10.1002/cpt.3721","DOIUrl":"https://doi.org/10.1002/cpt.3721","url":null,"abstract":"<p><p>Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment but are responsible for various immune-related adverse events (irAE). The impact of non-anticancer medications (comedications) on irAE occurrence remains largely unexplored. The objective of this study was to assess comedications associated with an increased reporting of irAE with ICIs. In this pharmacovigilance study, all individual case safety reports (ICSRs) involving ICIs reported in the World Health Organization international pharmacovigilance database Vigibase up to January 2024 were extracted. All suspect or interacting comedications were analyzed individually and as drug classes using Anatomical Therapeutic Chemical classification level 4. The primary outcome was the reporting odds ratio (ROR) of irAE in patients who received both an ICI and the comedication of interest, compared with ICI-treated patients who did not receive that comedication. Among 169,753 ICSRs involving an ICI, a total of 314,366 comedications were recorded, with 8,122 identified as \"suspect or interacting.\" Analysis shows an increased reporting of nephritis with proton pump inhibitors (PPI) (ROR = 29.62 [95% CI = 18.61-47.14]) and with non-steroidal anti-inflammatory drugs (ROR = 10.47 [95% CI = 4.15-26.41]), myositis with statins (ROR = 9.41 [95% CI = 3.50-25.30]), ketoconazole with hepatitis (ROR = 20.49 [95% CI = 1.53-274.17]) and autoimmune bullous disease with dipeptyl-peptidase-4 inhibitors (ROR = 46.42 [95% CI = 11.71-184.05]), among others. Various drugs, including PPI (ROR = 8.61 [95% CI = 3.48-21.26]), some anti-infectives (sulfamethoxazole, ROR = 31.31 [95% CI = 13.32-73.61], clavulanic acid, ROR = 18.12 [95% CI = 4.77-68.89]), allopurinol (ROR = 57.11 [95% CI = 11.27-289.39]) or levetiracetam (ROR = 14.91 [95% CI = 2.15-103.64]) were associated with serious cutaneous adverse reactions. Complementary analysis showed higher ROR in the ICI population versus without ICI for the association of nephritis with ibuprofen (ROR_ICI = 27.82 vs. ROR_{VigiBaseWithoutICI} = 3.56, ROR_ratio = 7.81 [95% CI = 1.23-49.50]) and myocarditis with influenza vaccine (ROR_ICI = 22.74 vs. ROR_{VigiBaseWithoutICI} = 0.66, ROR_ratio = 34.45 [95% CI = 1.66-723.24]), suggesting a synergistic toxicity. This study identified multiple comedications associated with an increased reporting of specific irAE. Some of them might be synergistic warranting further investigation.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiome-Informed Dosing: Exploring Gut Microbial Communities Impact on Mycophenolate Enterohepatic Circulation and Therapeutic Target Achievement.","authors":"Abdelrahman Saqr, Shen Cheng, Mahmoud Al-Kofahi, Christopher Staley, Pamala A Jacobson","doi":"10.1002/cpt.3740","DOIUrl":"https://doi.org/10.1002/cpt.3740","url":null,"abstract":"<p><p>Pharmacomicrobiomics is an emerging field due to important microbiome effects on pharmacokinetics and clinical outcomes. However, the application of this knowledge remains limited. Mycophenolic acid (MPA) is the primary active metabolite of the immunosuppressant, mycophenolate mofetil (MMF). MPA undergoes glucuronidation to form MPA glucuronide (MPAG) which is deglucuronidated by bacterial β-glucuronidases and reformed as MPA through enterohepatic circulation (EHC). We studied the stool microbiome effect on the pharmacokinetics of MPA, its metabolites, and EHC in hematopoietic cell transplant (HCT) recipients using a semi-mechanistic population pharmacokinetic model. Microbiome communities were identified using correlation network analysis, and their impact on pharmacokinetics was assessed using full fixed-effects modeling. Simulations were then conducted to evaluate MMF dosing regimens and to assess the impact of community abundance on EHC and MPA therapeutic target achievement. High abundance of Bacteroides uniformis-dominant and Bacteroides vulgatus-dominant communities was associated with higher EHC and an increase in MPA exposure. Low abundance of these communities was associated with a 52-80% and 4-83% lower EHC and MPA exposure, respectively. Simulations showed 70% of individuals with low abundance of these communities achieved the therapeutic target at the typical HCT MMF dose of 1,000 mg Q8 hours IV; however, ≥ 95% were within the therapeutic target at 1,250 mg Q8 hours or 1,750 mg Q12 hours. EHC accounted for 34% of the MPA area under the curve. Elimination of EHC reduced troughs by 100%. This work quantifies the microbiome's effect on pharmacokinetics, paving the way for future microbiome-informed dosing to optimize therapeutic target attainment.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FRAME: Framework for Real-World Evidence Assessment to Mitigate Evidence Uncertainties for Efficacy/Effectiveness - An Evaluation of Regulatory and Health Technology Assessment Decision Making.","authors":"Gianmario Candore, Claire Martin, Mack J Mills, Annabel Suter, Anna Lloyd, Danitza Chavez-Montoya, Diego Civitelli, Birgit Wolf, Paul Bolot, Juergen Wasem, Montse Soriano Gabarró, Panos G Kanavos, Mark Sculpher","doi":"10.1002/cpt.3713","DOIUrl":"https://doi.org/10.1002/cpt.3713","url":null,"abstract":"<p><p>Real-World Evidence (RWE) is increasingly used in submissions to regulatory agencies and health technology assessment bodies (HTAbs) to support the efficacy and effectiveness of new medicines and indications. However, there is limited information on the RWE characteristics that impact its role in approval and reimbursement decisions. To investigate these characteristics, we developed FRAME: a Framework for Real-world evidence Assessment to Mitigate Evidence uncertainties for efficacy/effectiveness. We compiled a list of medicinal product indications where RWE supported the efficacy of interventional trials or assessed effectiveness in observational settings. FRAME was applied to a prioritized subset of these submissions to authorities from North America, Europe, and Australia. For each product indication, we extracted information on characteristics describing the submission, clinical context, strength of evidence, and process factors from publicly available assessment reports. Of the 87 identified medicinal product indications, 15 were prioritized, covering 68 submissions and 76 RWE studies across 11 authorities in scope. Four main results emerged: (i) low granularity within assessment reports on the analyzed variables, limiting the learnings from analyzing them; (ii) variability in how RWE was assessed within and across regulatory agencies and HTAbs; (iii) a positive association between the proportion of positive comments from authorities on RWE studies and their impact on decision making. Particularly, a large effect size was consistently noted when RWE was considered primary evidence; and (iv) limited use of advanced RWE study designs. These findings support five recommendations to enhance shared learning on RWE, clarify its evidentiary value, and generate evidence to better support authorities' decision making.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing Acebutolol for Osteoporosis Treatment: Insights From Multi-Omics and Multi-Modal Data Analysis.","authors":"Dan-Yang Liu, Hui Shen, Jonathan Greenbaum, Qiao-Rong Yi, Shuang Liang, Yue Zhang, Jia-Chen Liu, Chuan Qiu, Lan-Juan Zhao, Qing Tian, Kuan-Jui Su, Zhe Luo, Li Wu, Xiang-He Meng, Hong-Mei Xiao, Yun Deng, Yang Li, Dragana Lovre, Vivian Fonseca, Fernando L Sanchez, Li-Jun Tan, Hong-Wen Deng","doi":"10.1002/cpt.3738","DOIUrl":"https://doi.org/10.1002/cpt.3738","url":null,"abstract":"<p><p>Osteoporosis is a common metabolic bone disease with aging, characterized by low bone mineral density (BMD) and higher fragility fracture risk. Although current pharmacological interventions provide therapeutic benefits, long-term use is limited by side effects and comorbidities. In this study, we employed driver signaling network identification (DSNI) and drug functional networks (DFN) to identify repurposable drugs from the Library of Integrated Network-Based Cellular Signatures. We constructed osteoporosis driver signaling networks (ODSN) using multi-omics data and developed DFN based on drug similarity. By integrating ODSN and DFN with drug-induced transcriptional responses, we screened 10,158 compounds and identified several drugs with strong targeting effects on ODSN. Mendelian randomization assessed potential causal links between cis-eQTLs of drug targets and BMD using genome-wide association study data. Our findings indicate four drugs, including Ruxolitinib, Alfacalcidol, and Doxercalciferol, may exert anti-osteoporosis effects. Notably, Acebutolol, a β-blocker for hypertension, has not previously been implicated in osteoporosis therapy. For validation, zebrafish osteoporosis models were established using Dexamethasone-induced bone loss, followed by treatment with Acebutolol hydrochloride and Alfacalcidol. Both compounds demonstrated significant protective effects against osteoporosis-related bone deterioration. Furthermore, a population-based data set, utilizing propensity score matching and analyzed via a generalized linear model, revealed that individuals taking β-blocker drugs exhibited significantly higher BMD than users of other cardiovascular medications. In summary, this study integrates multi-omics approaches, experimental validation, and real-world population data to propose acebutolol as a novel candidate for osteoporosis treatment. These findings warrant further mechanistic studies and clinical trials to evaluate its efficacy in osteoporosis management.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of PopPK and E-R Analyses toward Explaining Causal Link Between ADAMTS13 in Recombinant vs. Plasma-Based Therapies and Clinical Effects in cTTP.","authors":"Munjal Patel, Huijuan Xu, Olivier Barriere, Paul Diderichsen, Parth Patwari, Andy Z X Zhu, Jean François Marier, Thomas Peyret, Linda T Wang, Björn Mellgård, Wenping Wang, Indranil Bhattacharya","doi":"10.1002/cpt.3720","DOIUrl":"https://doi.org/10.1002/cpt.3720","url":null,"abstract":"<p><p>Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, potentially life-threatening condition caused by a deficiency of the blood enzyme ADAMTS13. Until now, ADAMTS13 replacement has been achieved with infusions of plasma or plasma-based therapies (PBT). However, the quantitative relationship between ADAMTS13 plasma activity and clinical manifestations is poorly understood. We therefore conducted integrated population pharmacokinetics (PopPK) analysis and exposure-response modeling based on three clinical trials of recombinant ADAMTS13 (rADAMTS13, Takeda Pharmaceuticals U.S.A., Inc.) in patients with cTTP. These aim to assess the clinical benefit of rADAMTS13, which at the proposed dose of 40 IU/kg provides ADAMTS13 peak levels of approximately 100% of normal levels. The PK model indicated that, besides body weight-based dosing, no further dose adjustment was required based on age or race. The only extrinsic covariates with a significant impact on ADAMTS13 plasma activity levels were dosing interval and treatment type (rADAMTS13 vs. PBT). The correlation between ADAMTS13 plasma activity levels and cTTP manifestations was investigated with three different exposure-response models. Increasing exposure to ADAMTS13, as measured by average activity over a one-to-two-week period, predicted the probability of disease manifestations, primarily assessed as thrombocytopenia. Model simulations predicted that >90% of patients treated with 40 IU/kg rADAMTS13 achieve an average ADAMTS13 plasma activity >13% of normal, which was shown to be highly protective against thrombocytopenia (>70% lower hazard). Similar results were observed for protection against elevation of lactate dehydrogenase, a marker of microangiopathic hemolytic anemia. Overall, these results support the use of rADAMTS13 treatment for patients with cTTP.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using Quantitative Approaches to Optimize Dosages for New Combinations and Subsequent Indications for Oncology Drugs.","authors":"Wei Gao, Jiang Liu, Cynthia J Musante, Hao Zhu, Matthew Thompson, Mirat Shah, Yanguang Cao, Vijay Ivaturi, Mark R Conaway, Dean Bottino, Donghua Yin, Dorothee Semiond, Aram Oganesian, Mark J Ratain, Chunze Li, Li Zhu, Ying C Ou, Xiling Jiang, Jonathan Vallejo, Rajanikanth Madabushi, Qi Liu, Marc Theoret, Atiqur Rahman, Brian Booth, Olanrewaju Okusanya, Bernadette E Johnson-Williams, Stacy S Shord","doi":"10.1002/cpt.3725","DOIUrl":"https://doi.org/10.1002/cpt.3725","url":null,"abstract":"<p><p>Ongoing efforts to optimize the dosages of oncology drugs have largely focused on the initial indication, with emphasis placed on maximizing the utility of all available evidence to improve dose finding, dose selection, and trial design; however, optimizing dosages for new combinations or subsequent indications is more complex and warrants further discussion. For example, the dose-response (DR) or exposure-response (ER) relationships can change when multiple drugs are used (combination therapies) and can differ between tumor types, patient populations, and treatment settings (subsequent indications). Quantitative approaches can help address the challenges of optimizing dosages for new combinations or subsequent indications. To further this dialogue, the US Food and Drug Administration's Office of Clinical Pharmacology and the International Society of Pharmacometrics co-sponsored a workshop to discuss the development of investigational and approved drugs in new combinations or for subsequent indications using model-informed approaches to investigate, support, and select optimized dosages for oncology drugs.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress in Pharmacogenomics Implementation in the United States: Barrier Erosion and Remaining Challenges.","authors":"D Max Smith, Michael P Douglas, Christina L Aquilante, Patricia A Deverka, Beth Devine, Henry M Dunnenberger, Philip E Empey, Daniel L Hertz, Andrew A Monte, Ann M Moyer, Jai N Patel, Victoria M Pratt, Loren Saulsberry, Stuart A Scott, Deepak Voora, Erica L Woodahl, Michelle Whirl-Carrillo, Akinyemi Oni-Orisan","doi":"10.1002/cpt.3736","DOIUrl":"https://doi.org/10.1002/cpt.3736","url":null,"abstract":"<p><p>Barriers to incorporating pharmacogenetics into routine clinical practice in the United States are well documented. Initial surveys by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2009 and 2010 identified barriers across four key domains that have hindered the widespread adoption of clinical pharmacogenetic testing. These are presented verbatim as: (i) absence of a definition of the processes required to interpret genotype information and to translate genetic information into clinical actions; (ii) need for recommended drug/gene pairs to implement clinically now; (iii) clinician resistance to consider pharmacogenetic information at the bedside; and (iv) concerns about test costs and reimbursement. Over time, many of these challenges have been overcome, and clinical pharmacogenetic testing has subsequently reached broader implementation. Despite this progress, several barriers remain that block further adoption. This narrative review used authors' expertise and experience to identify and describe current barriers to pharmacogenetic implementation across seven domains in the United States: equity and inclusion; guidelines and supporting evidence; regulatory agency oversight; payer coverage and insurance; availability of quality pharmacogenetic tests; electronic health records; and provider and patient education. Within each domain, it revisits past successes and challenges and explores remaining barriers. We also propose solutions to address ongoing challenges across these domains, including further expansion of recommendations beyond pharmacogenetic-specific guidelines, standards for designing clinical decision support tools, and broader pharmacogenetics education. Addressing these remaining obstacles directs work to enable broader adoption of clinical pharmacogenetic implementation to ultimately improve patient outcomes.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP2C19 Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention in the Million Veteran Program.","authors":"Catherine Chanfreau-Coffinier, Kevin A Friede, Mary E Plomondon, Kyung Min Lee, Zhenyu Lu, Tia Dinatale, Scott L DuVall, Jason L Vassy, Stephen W Waldo, John H Cleator, Thomas M Maddox, Daniel J Rader, Themistocles L Assimes, Scott M Damrauer, Philip S Tsao, Kyong-Mi Chang, Deepak Voora, Julie A Lynch, Jay Giri, Sony Tuteja","doi":"10.1002/cpt.3741","DOIUrl":"10.1002/cpt.3741","url":null,"abstract":"<p><p>CYP2C19 loss-of-function (LOF) alleles decrease the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). The impact of genotype in patients undergoing PCI for stable ischemic heart disease (SIHD) in real-world populations is less clear. We determined time to major adverse cardiac event (MACE), defined as the composite of cardiovascular death, stroke, or myocardial infarction, within 12 months following PCI in the VA Million Veteran Program (MVP) participants treated with clopidogrel from 1/1/2009 to 9/30/2017. Among 9061 Veterans (mean age 66.4 ± 8.7 years, 98% male, 13% Black); 43% had ACS, 57% had SIHD, and 28% carried a CYP2C19 LOF allele. In total, 619 patients (6.8%) experienced MACE, 317 (8.2%) in the ACS group and 302 (5.8%) in the SIHD group. Overall, a trend toward increased MACE risk was seen in the LOF carriers vs. non-carriers (adjusted hazard ratio [aHR] 1.13, confidence interval [95% CI] 0.98-1.31, P = 0.097), with a stronger risk among those presenting with ACS (aHR 1.20, 95% CI 0.98-1.47; P = 0.083). In post hoc analyses, LOF was associated with a significantly increased risk of MACE among younger (< 66 years) patients with ACS (aHR 1.41 [1.04-1.91], P = 0.028); however, no difference in risk was observed among older patients (aHR 1.07, 95% CI 0.80-1.40, P = 0.676). There was no impact of genotype in patients with SIHD (aHR 1.09, 95% CI 0.82-1.44, P = 0.565). Clinical factors may be more important than CYP2C19 genotype in determining the risk of MACE in older Veterans treated with clopidogrel undergoing PCI for ACS.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}