Cts-Clinical and Translational Science最新文献

{"title":"Optimized fosfomycin regimens for treating carbapenem-resistant Acinetobacter baumannii in critically ill patients with varying degrees of renal function","authors":"Nattapong Tidwong,&nbsp;Anan Chanruang,&nbsp;Suthanya Chupradit,&nbsp;Suzanne L. Parker,&nbsp;Pannee Leelawattanachai,&nbsp;Poramed Winichakoon,&nbsp;Baralee Punyawudho","doi":"10.1111/cts.70038","DOIUrl":"10.1111/cts.70038","url":null,"abstract":"<p>Fosfomycin has been used to treat carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) infections. However, there is insufficient information on dosage adjustment among critically ill patients with renal impairment. This study aims to evaluate the attainment of PK/PD targets for different dosage regimens of CRAB treatment in critically ill patients based on their renal function. Monte Carlo simulations were conducted to assess the probability of achieving time above the minimum inhibitory concentration (T &gt; MIC) of 80% and 100% and to determine the cumulative fraction response (CFR) against institutional MICs. Our results demonstrated that administering fosfomycin 20–24 g/day to individuals with normal renal function (CrCl ≥60 mL/min) achieved the target at a MIC of ≤64 and ≤32 μg/mL during the first 24 h of treatment and at steady state, respectively. Notably, those with renal impairment achieved higher MIC values at a steady state despite dosage reduction. None of the regimens reached the target CFR. Our study suggested that administering fosfomycin at least 20 g/day to those with normal renal function provides sufficient exposure throughout the treatment course when the MIC value is ≤32 μg/mL. Less aggressive dosing regimens are advisable for patients with renal impairment. Additional clinical studies are necessary to verify our suggestions.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331716","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}

{"title":"Noninvasive skin swab analysis detects environmental drug exposure of pharmacy staff","authors":"Samantha Thompson,&nbsp;Samvel Abelyan,&nbsp;Morgan Panitchpakdi,&nbsp;Jasmine Zemlin,&nbsp;Sydney Thomas,&nbsp;Haoqi Nina Zhao,&nbsp;Pieter C. Dorrestein,&nbsp;Shirley M. Tsunoda","doi":"10.1111/cts.70022","DOIUrl":"https://doi.org/10.1111/cts.70022","url":null,"abstract":"<p>The skin is complex with multiple layers serving protective, regulatory, and detective functions. The skin hosts chemicals originating from consumption, synthesis, and the environment. Skin chemicals can provide insight into one's daily routine or their level of safety in a work environment. The goal of this study was to investigate the utility of noninvasive skin swabs to detect drugs in a pharmacy setting and to determine whether drugs are transferred to the skin of pharmacy staff. To answer this question, skin swabs were collected from healthy pharmacy staff workers and healthy non-pharmacy individuals and analyzed via untargeted liquid chromatography–tandem mass spectrometry (LC–MS/MS). Drugs were annotated through library matching against the GNPS community spectral library. We then used questionnaire data to exclude medications that participants took orally or applied topically and focused on the drugs participants were exposed to in the work setting. Overall, pharmacy staff had a higher number and variety of medications on their skin as compared with healthy individuals who did not work in a pharmacy. In addition, we identified some chemicals such as <i>N</i>,<i>N</i>-Diethyl-metatoluamide on a large number of subjects in both experimental and control groups, indicating environmental exposure to this compound may be ubiquitous and long-lasting.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324427","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}

{"title":"Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers","authors":"William K. Schmidt,&nbsp;Irene Cortés-Puch,&nbsp;Cindy B. McReynolds,&nbsp;Glenn E. Croston,&nbsp;Sung Hee Hwang,&nbsp;Jun Yang,&nbsp;Theresa L. Pedersen,&nbsp;Karen M. Wagner,&nbsp;Theresa T. Pham,&nbsp;Thomas Hunt,&nbsp;Bruce D. Hammock","doi":"10.1111/cts.70033","DOIUrl":"https://doi.org/10.1111/cts.70033","url":null,"abstract":"<p>Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5–2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8–24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273137","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}

{"title":"Inadequate representation of individuals of African ancestry in pharmacogenetics of tamoxifen research","authors":"Keneuoe Cecilia Nthontho,&nbsp;Andrew Khulekani Ndlovu,&nbsp;Giacomo Maria Paganotti","doi":"10.1111/cts.70029","DOIUrl":"10.1111/cts.70029","url":null,"abstract":"<p>We read with great interest the paper titled “Pharmacogenetics of tamoxifen in breast cancer patients of African descent: Lack of data” by Kruger et al.<span>¹</span> We agree with the authors, on their analysis and conclusions from their work. Indeed, no studies in Africans or in populations of African ancestry have looked and successfully demonstrated any association between inherited variants in genes underlying tamoxifen metabolism and clinical outcomes. Actually, only a very limited number of studies both among Africans and/or subjects of African descent explored the association between genetic variants of <i>CYP2D6</i> and tamoxifen/endoxifen concentration, association that has been proved and confirmed.<span>²</span> Another level of complexity is that <i>CYP2D6</i> “star alleles” influence tamoxifen/endoxifen level concentrations, but a significant number of African polymorphisms have not been fully explored and validated. A point of interest and possible evaluation could also be that whereas women of African descent in the West may be an appropriate proxy for sub-Saharan African populations, the disease landscape of women in sub-Saharan Africa may differ from those from other continents. In fact, it should be taken into consideration the standing co-infections with parasitic, bacterial and viral diseases, and their treatments, together with malnutrition. This may complicate the general picture and the interactions between drugs, diseases and pharmacogenetics of transport and metabolism. Additionally, there are numerous studies assessing the role of the genes encoding for enzymes relevant for tamoxifen metabolism, but the present literature points in the context of antimalarial and antiretroviral drugs.<span>³</span> These findings may provide very useful information for allele frequencies that can be translated to infer tamoxifen metabolism.</p><p>Here, we want to stress that <i>lack of data</i> should be addressed with appropriate clinical studies in subjects from African countries and among different African ethnic groups, as the available dosing guidelines are likely to be inappropriate for most Africans.<span>⁴</span> Nowadays, “omics” technologies and novel approaches allow for a deep understanding of these phenomena, also in the context of Africa, and this constitute a mandatory goal for scientists in the area.</p><p>Also, it is important to note that with all the concepts that have been raised, there is still the issue of <i>lack of funding</i> for research in pharmacogenetics for the continent, as well as initiatives to set up organizations that could best aid in providing the necessary visibility and resources to shape up the story of pharmacogenetics in Africans and populations of African ancestry.</p><p>No funding was received for this work.</p><p>The authors declared no competing interests for this work.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265801","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}

{"title":"Correction to Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate-to-severe atopic dermatitis: Results from two terminated phase II trials","authors":"","doi":"10.1111/cts.70026","DOIUrl":"https://doi.org/10.1111/cts.70026","url":null,"abstract":"<p>Concentration time proles of total IL-33 in East Asian and non-East Asian patients during the study period in the (A) dose-ranging study and (B) proof-of-concept study.</p><p>In Figure S4 (all panels), the Y-axis label should be ng/mL, not mg/L.</p><p>We apologize for this error.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273136","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}

{"title":"Computational drug discovery pipelines identify NAMPT as a therapeutic target in neuroendocrine prostate cancer","authors":"Weijie Zhang,&nbsp;Adam Lee,&nbsp;Lauren Lee,&nbsp;Scott M. Dehm,&nbsp;R. Stephanie Huang","doi":"10.1111/cts.70030","DOIUrl":"10.1111/cts.70030","url":null,"abstract":"<p>Neuroendocrine prostate cancer (NEPC) is an aggressive advanced subtype of prostate cancer that exhibits poor prognosis and broad resistance to therapies. Currently, few treatment options are available, highlighting a need for new therapeutics to help curb the high mortality rates of this disease. We designed a comprehensive drug discovery pipeline that quickly generates drug candidates ready to be tested. Our method estimated patient response to various therapeutics in three independent prostate cancer patient cohorts and selected robust candidate drugs showing high predicted potency in NEPC tumors. Using this pipeline, we nominated NAMPT as a molecular target to effectively treat NEPC tumors. Our in vitro experiments validated the efficacy of NAMPT inhibitors in NEPC cells. Compared with adenocarcinoma LNCaP cells, NAMPT inhibitors induced significantly higher growth inhibition in the NEPC cell line model NCI-H660. Moreover, to further assist clinical development, we implemented a causal feature selection method to detect biomarkers indicative of sensitivity to NAMPT inhibitors. Gene expression modifications of selected biomarkers resulted in changes in sensitivity to NAMPT inhibitors consistent with expectations in NEPC cells. Validation of these markers in an independent prostate cancer patient dataset supported their use to inform clinical efficacy. Our findings pave the way for new treatments to combat pervasive drug resistance and reduce mortality. Furthermore, this research highlights the use of drug sensitivity-related biomarkers to understand mechanisms and potentially indicate clinical efficacy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265802","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}

{"title":"Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis","authors":"Nabila Ibnou Zekri Lassout,&nbsp;Vishal Goyal,&nbsp;Edrich Krantz,&nbsp;Francois Simon,&nbsp;Anouk Neven,&nbsp;Johanna Eriksson,&nbsp;Amaria Saayman,&nbsp;Vijay Satam,&nbsp;Carol Ruffell,&nbsp;Sarika Victor,&nbsp;Marylore Chenel,&nbsp;Aljosa Celebic,&nbsp;Henri Caplain,&nbsp;Jean-Yves Gillon,&nbsp;Abhijit Deshmukh,&nbsp;Amit Antarkar,&nbsp;Eric Sjögren,&nbsp;Isabela Ribeiro","doi":"10.1111/cts.13908","DOIUrl":"https://doi.org/10.1111/cts.13908","url":null,"abstract":"<p>Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance. We recently reported the relative bioavailability in fasting conditions of a sustained release (SR) oral pellet formulation of 5-FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5-FC SR formulation in a single dose (2 × 3000 mg), relative to 5-FC IR tablets (Ancotil®; 1500 mg b.i.d.) in healthy participants in fed conditions. This randomized, two-period crossover study was conducted in South Africa to confirm the dose of the identified 5-FC SR formulation for a twice-daily 5-FC regimen in patients. Thirty-six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. <i>C</i>_max and AUC_{(0–<i>t</i>)} for the SR formulation (49.2 ± 10.49 μg/mL and 640.4 ± 126.4 h.μg/mL, respectively) were significantly higher than for the IR formulation (36.8 ± 7.61 μg/mL and 456.6 ± 72.8 h.μg/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000 mg SR pellets would show a good overlap with the IR product (3000 mg b.i.d), thus 6000 mg SR 5-FC b.i.d. in fasting conditions is recommended.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13908","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244818","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}

{"title":"Paired comparisons of venetoclax concentration in cerebrospinal fluid, bone marrow, and plasma in acute leukemia patients","authors":"Yuan Jian,&nbsp;Feifei Han,&nbsp;Ying Zhu,&nbsp;Chuanying Geng,&nbsp;Yanru Zhang,&nbsp;Yin Wu,&nbsp;Yun Leng,&nbsp;Wenming Chen,&nbsp;Zhuoling An,&nbsp;Hong-Hu Zhu","doi":"10.1111/cts.70006","DOIUrl":"https://doi.org/10.1111/cts.70006","url":null,"abstract":"<p>Venetoclax, a small molecule inhibitor of BCL-2, has demonstrated efficacy in treating acute leukemias and has been recommended as one of the first-line anti-leukemia therapies. Although venetoclax has been suggested to probably possess the ability to penetrate the central nervous system (CNS), current data to elucidate the characteristics of venetoclax in cerebrospinal fluid (CSF), bone marrow (BM), and plasma are still lacking. This study investigated the real-world characteristics of venetoclax concentrations in CSF, BM, and plasma in acute leukemia patients. Thirteen acute leukemia patients treated with venetoclax were included, with paired samples of CSF, BM, and plasma collected and venetoclax concentrations measured using LC–MS/MS. With the results, the median venetoclax concentrations were 2030 ng/mL in plasma, 16.7 ng/mL in CSF, and 1390 ng/mL in BM. The percentages of CSF/plasma and BM/plasma were 0.74% and 70.37%, respectively. While no direct correlation was observed between CSF and plasma venetoclax levels, there was a trend toward an improved CSF/plasma percentage over time following the last administration of venetoclax. In contrast, a strong correlation was found between BM and plasma levels. This study demonstrated that venetoclax could reach its effective concentration in most patients, suggesting its potential clinical utility in the management of CNS involvement in acute leukemia.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245019","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}

{"title":"Drug–drug interactions of icenticaftor (QBW251) with a 5-probe cytochrome P450 cocktail and oral contraceptives","authors":"Felix Huth,&nbsp;Ulrike Glaenzel,&nbsp;Anton Drollmann,&nbsp;Wendy Weis,&nbsp;Julia Zack,&nbsp;Lidiya Bebrevska","doi":"10.1111/cts.70028","DOIUrl":"https://doi.org/10.1111/cts.70028","url":null,"abstract":"<p>A drug–drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor (QBW251) on the pharmacokinetics (PK) of a 5-probe cytochrome P450 (CYP) substrate cocktail, guided by in vitro studies in human hepatocytes and liver microsomes. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. The static-mechanistic DDI assessment indicated that icenticaftor may moderately induce the metabolic clearance of co-medications metabolized by CYP3A4 (area under the concentration–time curve [AUC] ratio: 0.47) and potentially CYP2C; icenticaftor may also weakly inhibit the metabolic clearance of co-medications metabolized by CYP1A2 and CYP3A4 (AUC ratio: 1.35 and 1.86, respectively) and moderately inhibit CYP2B6 (AUC ratio: 2.11). In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 (AUC ratio: 3.35) and CYP2C19 (AUC ratio: 2.70). As expected from the results of the in vitro studies, weak induction was observed for CYP3A4 (AUC ratio: 0.51) and CYP2C8 (AUC ratio: 0.66). In the OC DDI study, co-administration of icenticaftor 450 mg b.i.d. with monophasic OC containing 30-μg EE and 150-μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle-stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or patients using OCs.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245020","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}

{"title":"Prevalence of actionable pharmacogenetic variants and high-risk drug prescriptions: A Swiss hospital-based cohort study","authors":"Flavia Hodel,&nbsp;Maria B. De Min,&nbsp;Christian Wandall Thorball,&nbsp;Claire Redin,&nbsp;Peter Vollenweider,&nbsp;François Girardin,&nbsp;Jacques Fellay","doi":"10.1111/cts.70009","DOIUrl":"https://doi.org/10.1111/cts.70009","url":null,"abstract":"<p>Drug type and dosing recommendation have been designed and optimized based on average response in the general population. Yet, there is significant inter-individual variability in drug response, which results in treatment inefficacy or adverse drug reactions in a subset of patients. This is partly due to genetic factors that typically affect drug metabolism or clearance. To verify the relevance and applicability of international pharmacogenetic guidelines in the Swiss population, we genotyped 1533 patients from a hospital-based biobank who received at least 30 different drugs, as documented in their electronic health record. We then assessed the prevalence of clinically actionable variants in 13 high-risk pharmacogenes. We compared the allele frequencies obtained in the hospital-based cohort with those of a Swiss population-based cohort of 4791 individuals. The prevalence of clinically actionable variants was comparable between the two cohorts, with most study participants (97.3%) carrying at least one actionable pharmacogenetic variant. We then assessed the frequency of high-risk prescriptions due to actionable gene–drug interactions and observed that 31% of patients in the hospital-based cohort were prescribed at least one drug for which they carried a high-risk variant, and for which international guidelines recommend a change of drug or dosage. Our analysis confirms the high prevalence of actionable pharmacogenetic variants in the Swiss population. It also shows that a substantial minority of patients are exposed to drugs for which they carry potentially problematic variants. Implementing a genetically informed approach to drug prescribing could have a positive impact on the quality of healthcare delivery.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174207","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}