Cts-Clinical and Translational Science最新文献

{"title":"Increasing acceptance of AI-generated digital twins through clinical trial applications","authors":"Anna A. Vidovszky,&nbsp;Charles K. Fisher,&nbsp;Anton D. Loukianov,&nbsp;Aaron M. Smith,&nbsp;Eric W. Tramel,&nbsp;Jonathan R. Walsh,&nbsp;Jessica L. Ross","doi":"10.1111/cts.13897","DOIUrl":"10.1111/cts.13897","url":null,"abstract":"<p>Today's approach to medicine requires extensive trial and error to determine the proper treatment path for each patient. While many fields have benefited from technological breakthroughs in computer science, such as artificial intelligence (AI), the task of developing effective treatments is actually getting slower and more costly. With the increased availability of rich historical datasets from previous clinical trials and real-world data sources, one can leverage AI models to create holistic forecasts of future health outcomes for an individual patient in the form of an AI-generated digital twin. This could support the rapid evaluation of intervention strategies in silico and could eventually be implemented in clinical practice to make personalized medicine a reality. In this work, we focus on uses for AI-generated digital twins of clinical trial participants and contend that the regulatory outlook for this technology within drug development makes it an ideal setting for the safe application of AI-generated digital twins in healthcare. With continued research and growing regulatory acceptance, this path will serve to increase trust in this technology and provide momentum for the widespread adoption of AI-generated digital twins in clinical practice.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749569","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":"Pharmacokinetic drug–drug interactions of JBPOS0101 mediated by cytochrome P450 3A4 and UDP-glucuronosyltransferases","authors":"Sejung Hwang,&nbsp;Yong Moon Choi,&nbsp;Myoung-Seok Kim,&nbsp;SeungHwan Lee","doi":"10.1111/cts.13892","DOIUrl":"10.1111/cts.13892","url":null,"abstract":"<p>JBPOS0101 is a new antiepileptic drug and is a substrate of UDP-glucuronosyltransferases (UGTs) in in vitro test. In vitro experiments showed different results regarding whether JBPOS0101 induces (EC₅₀ 136 μM) or inhibits (IC₅₀ 95.4–386.5 μM) cytochrome P450 (CYP) 3A4. As co-medication of JBPOS0101 and carbamazepine (CBZ) is expected in clinical settings, drug–drug interactions (DDIs) between them should be determined. This study aimed to investigate pharmacokinetic (PK) interactions of JBPOS0101 influenced by CYP3A4 and UGTs using midazolam (MDZ) and CBZ. A two-cohort, open-label, fixed-sequence study was conducted in healthy Koreans. In cohort A, subjects received MDZ IV alone, and then JBPOS0101 were co-administered with MDZ after oral doses of JBPOS0101 for 7 days. In cohort B, multiple doses of JBPOS0101 and CBZ were administered respectively, and subjects received both together for 7 days. Serial blood samples were collected for PK analysis. When MDZ and JBPOS0101 were co-administered, the systemic exposure of MDZ decreased by 30%. Meanwhile, JBPOS0101 did not significantly changed the PK of CBZ. CBZ decreased the systemic exposure of JBPOS0101 at steady state by 40%, respectively. With IV administration of MDZ, JBPOS0101 acted as a weak inducer of hepatic CYP3A4 and decreased systemic exposure of MDZ. The ability of JBPOS0101 to similarly modulate gut CYP3A4 activity will require further evaluation. Co-administration of multiple doses of JBPOS0101 and CBZ did not significantly alter CBZ pharmacokinetics, but the clinical impact of decreased systemic exposure of JBPOS0101 by CBZ should be further considered.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11260762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735604","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":"PBPK-led assessment of antimalarial drugs as candidates for Covid-19: Simulating concentrations at the site of action to inform repurposing strategies","authors":"Nada Abla,&nbsp;Lisa M. Almond,&nbsp;Jennifer J. Bonner,&nbsp;Naomi Richardson,&nbsp;Timothy N. C. Wells,&nbsp;Jörg J. Möhrle","doi":"10.1111/cts.13865","DOIUrl":"10.1111/cts.13865","url":null,"abstract":"<p>The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID-19) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro activity does not always translate to clinical efficacy across a therapeutic dose range. This study applied available, verified, physiologically based pharmacokinetic (PBPK) models for pyronaridine, amodiaquine, and its active metabolite N-desethylamodiaquine (DEAQ) to predict drug concentrations in lung tissue relative to plasma or blood in the default healthy virtual population. Lung exposures were compared to published data across the reported range of in vitro EC₅₀ values against SARS-CoV-2. In the multicompartment permeability-limited PBPK model, the predicted total <i>C</i>_max in lung mass for pyronaridine was 34.2 μM on Day 3, 30.5-fold greater than in blood (1.12 μM) and for amodiaquine was 0.530 μM, 8.83-fold greater than in plasma (0.060 μM). In the perfusion-limited PBPK model, the DEAQ predicted total <i>C</i>_max on Day 3 in lung mass (30.2 μM) was 21.4-fold greater than for plasma (1.41 μM). Based on the available in vitro data, predicted drug concentrations in lung tissue for pyronaridine and DEAQ, but not amodiaquine, appeared sufficient to inhibit SARS-CoV-2 replication. Simulations indicated standard dosing regimens of pyronaridine-artesunate and artesunate-amodiaquine have potential to treat COVID-19. These findings informed repurposing strategies to select the most relevant compounds for clinical investigation in COVID-19. Clinical data for model verification may become available from ongoing clinical studies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13865","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141635585","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":"How debunking biases in research and development decisions could lead to more equitable healthcare?","authors":"Benjamin Weber,&nbsp;Issam Zineh,&nbsp;Richard Lalonde,&nbsp;Sandra A. G. Visser","doi":"10.1111/cts.13880","DOIUrl":"10.1111/cts.13880","url":null,"abstract":"<p>Decades of research have demonstrated that a variety of cognitive biases can affect our judgment and ability to make rational decisions in personal and professional environments. The lengthy, risky, and costly nature of pharmaceutical research and development (R&amp;D) makes it vulnerable to biased decision-making. Moreover, cognitive biases can play a role in regulatory and clinical decision-making, the latter impacting diagnostic and treatment decisions in the therapeutic use of medicines. These inherent and/or institutionalized biases (e.g., in assumptions, data, or decision-making practices) could conceivably contribute to health inequities. In this mini-review, we provide a broad perspective on how cognitive biases can affect pharmaceutical R&amp;D, regulatory evaluation, and therapeutic decision-making. Example approaches to mitigate the effect of common biases in the development, approval, and use of new therapeutics, such as quantitative decision criteria, multidisciplinary reviews, regulatory and treatment guidelines, and evidence-based clinical decision support systems are illustrated. Mitigating the impact of cognitive biases could increase pharma R&amp;D efficiency, change the perspective and prioritization of unmet medical needs, increase representativeness and quality of evidence generated through clinical trials and real-world research, leading to higher quality insights and more effective medication use, and as such could eventually contribute to more equitable healthcare.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13880","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629185","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":"Pharmacokinetics and safety of mavacamten in healthy Chinese participants with different CYP2C19 phenotypes","authors":"Xiaojie Wu,&nbsp;Nanye Chen,&nbsp;Peiwen Hsu,&nbsp;Jing Sun,&nbsp;Wenting Li,&nbsp;Qi Wang,&nbsp;Merali Samira,&nbsp;Qiong Wei,&nbsp;Jicheng Yu,&nbsp;Guoying Cao,&nbsp;Haijing Yang,&nbsp;Lili Wang,&nbsp;Jingjing Wang,&nbsp;Yi Jin,&nbsp;Wei Liu,&nbsp;Jufang Wu,&nbsp;Jinjie He,&nbsp;Cheng Lyu,&nbsp;Jing Zhang","doi":"10.1111/cts.13877","DOIUrl":"10.1111/cts.13877","url":null,"abstract":"<p>Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II–III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open-label, parallel-group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, <i>C</i>_max was reached within a median <i>T</i>_max of 0.6–1.5 h, indicating rapid absorption. Inter-individual variability was moderate, and individuals carrying non-functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half-life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13877","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629186","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":"Reduced hepatic impairment study to evaluate pharmacokinetics and safety of zavegepant and to inform dosing recommendation for hepatic impairment","authors":"Rajinder Bhardwaj,&nbsp;Mary K. Donohue,&nbsp;Jennifer Madonia,&nbsp;Beth Morris,&nbsp;Thomas C. Marbury,&nbsp;Kyle T. Matschke,&nbsp;Robert Croop,&nbsp;Richard Bertz,&nbsp;Jing Liu","doi":"10.1111/cts.13813","DOIUrl":"10.1111/cts.13813","url":null,"abstract":"<p>Zavegepant, a high-affinity, selective, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is approved in the United States for acute treatment of migraine in adults. The effects of moderate hepatic impairment (8 participants with Child-Pugh score 7–9 points) on the pharmacokinetics of a single 10-mg intranasal dose of zavegepant versus eight matched participants with normal hepatic function were evaluated in a phase I study. Pharmacokinetic sampling determined total and unbound plasma zavegepant concentrations. Moderate hepatic impairment increased the exposure of total zavegepant (~2-fold increase in AUC_0–inf and 16% increase in C_max) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC_0−inf and C_max were 193% (90% confidence interval [CI]: 112, 333; <i>p</i> = 0.051) and 116% (90% CI: 69, 195; <i>p</i> = 0.630), respectively. The geometric mean fraction unbound of zavegepant was similar for participants with moderate hepatic impairment (0.13; coefficient of variation [CV] 13.71%) versus those with normal hepatic function (0.11; CV 21.43%). Similar exposure findings were observed with unbound zavegepant versus normal hepatic function (~2.3-fold increase in AUC_0−inf and 39% increase in C_max). One treatment-emergent adverse event (mild, treatment-related headache) was reported in a participant with normal hepatic function. No dosage adjustment of intranasal zavegepant is required in adults with mild or moderate hepatic impairment.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13813","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629187","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":"Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole","authors":"Sylvia D. Klomp,&nbsp;Anette Veringa,&nbsp;Jan-Willem C. Alffenaar,&nbsp;Mark G. J. de Boer,&nbsp;Lambert F. R. Span,&nbsp;Henk-Jan Guchelaar,&nbsp;Jesse J. Swen","doi":"10.1111/cts.13887","DOIUrl":"10.1111/cts.13887","url":null,"abstract":"<p>Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between <i>CYP2C19</i> genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, <i>CYP2C19</i> genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of <i>CYP2C19</i> genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (&gt;50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their <i>CYP2C19</i> genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the <i>CYP2C19</i> genotypes.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13887","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621697","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":"The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first-in-class ACKR3/CXCR7 antagonist, ACT-1004-1239","authors":"Christine Huynh,&nbsp;Jasper Dingemanse,&nbsp;Henriette E. Meyer zu Schwabedissen,&nbsp;Marlene Fonseca,&nbsp;Patricia N. Sidharta","doi":"10.1111/cts.13883","DOIUrl":"10.1111/cts.13883","url":null,"abstract":"<p>Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug–drug interactions (DDIs). ACT-1004-1239 is a potent and selective, first-in-class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT-1004-1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single-dose ACT-1004-1239 in healthy male subjects. In the open-label, fixed-sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT-1004-1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT-1004-1239 in the second period. We report a median of difference in <i>t</i>_max (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of <i>C</i>_max and AUC_0−∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of <i>t</i>_1/2 was 1.46 (1.26, 1.70). Both treatments were well-tolerated with an identical incidence in subjects reporting treatment-emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to &lt;5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13883","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621698","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":"Pharmacokinetics of Sofosbuvir/Velpatasvir and efficacy of an alternate-day treatment in hemodialysis patients with chronic hepatitis C infection","authors":"Pajaree Chariyavilaskul,&nbsp;Nantaporn Prompila,&nbsp;Supeecha Wittayalertpanya,&nbsp;Sookruethai Lekhyananda,&nbsp;Wisit Prasithsirikul,&nbsp;Thananda Trakarnvanich,&nbsp;Somboon Jeenapongsa,&nbsp;Paweena Susantitaphong,&nbsp;Stephen Kerr,&nbsp;Anchalee Avihingsanon,&nbsp;Pisit Tangkijvanich,&nbsp;Kearkiat Praditpornsilpa","doi":"10.1111/cts.13884","DOIUrl":"10.1111/cts.13884","url":null,"abstract":"<p>Sofosbuvir/Velpatasvir (SOF/VEL) is a combination drug used for chronic hepatitis C (HCV) infection. However, limited information exists regarding the pharmacokinetics of SOF/VEL and its metabolites in hemodialysis patients. We conducted a prospective investigation of the pharmacokinetic parameters of SOF/VEL after a single dose of SOF/VEL (400/100 mg) on days with and without dialysis in 12 Thai hemodialysis patients with chronic HCV infection, who had been undergoing hemodialysis for a duration of 0.5–20 years. Blood samples were collected before dose (0) and 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, and 12.0 h after dose. Dialysate samples were also collected before dose (0) and 1.0, 2.0, 3.0, and 4.0 h after dose. Plasma and dialysate samples were quantified for SOF and its metabolite, GS-331007, and VEL concentrations using a fully validated LCMS technique. In addition, a preliminary efficacy study was conducted using the proposed SOF/VEL dose reduction regimen in all patients. No differences in SOF/VEL PK parameters between on- and off-dialysis studies. On the contrary, GS-331007 exhibited a 30% reduction in the area under the plasma concentration–time curve from time 0 to 24 h (AUC_0-24h) on dialysis days compared with non-dialysis days (AUC_0-24h ratio 0.68 vs. 1.04, respectively). The dialysis clearance of SOF and GS-331007 was 9.35 (8.72–15.11) and 8.89 (8.52–14.07) mL/min, respectively. Subsequently, an alternate-day regimen of SOF/VEL (400/100 mg) was administered for 12 weeks, resulting in an undetectable plasma HCV viral load without side effects. Further clinical studies are warranted to validate the efficacy and safety of our proposed dose reduction regimen.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13884","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617508","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":"Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States: A comparative study of accelerated approvals","authors":"Hayase Hakariya,&nbsp;Frank Moriarty,&nbsp;Akihiko Ozaki,&nbsp;Shai Mulinari,&nbsp;Hiroaki Saito,&nbsp;Tetsuya Tanimoto","doi":"10.1111/cts.13879","DOIUrl":"10.1111/cts.13879","url":null,"abstract":"<p>Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross-sectional study, we considered 23 indications of cancer drugs that received accelerated approval by the US Food and Drug Administration (FDA) but were subsequently withdrawn as of April 2023. Our investigation extended to assessing the regulatory status of these accelerated approvals in the European Union (EU) and Japan, examining relevant regulatory documents and identifying factors contributing to the withdrawal in the United States. Comparing regions, we found that for 52% (12/23) and 30% (7/23) of withdrawn accelerated approvals in the United States, sponsors had also sought marketing authorization from the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), respectively. As of the April 30, 2023 study cutoff date, 83% (10/12) of drug–indication pairs remained approved by the EMA, while the PMDA retained 100% (7/7). For these indications, the time from FDA withdrawal until the study cutoff date ranged from 0.23 years to 11.45 years for EMA approvals (median: 1.28 years) and 1.10 years to 11.45 years for PMDA approvals (median: 3.22 years). These findings highlight substantial regulatory discrepancies concerning cancer drugs with unconfirmed benefits. Addressing these discrepancies may involve requiring pharmaceutical companies to confirm clinical benefits using more robust end points and fostering international harmonization in regulators' assessment.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13879","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141581447","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}