Clinical Pharmacology & Therapeutics最新文献

{"title":"Innovative Drugs Approved in China After Registration Classification Reform: Current Status, Disparities, and Challenges.","authors":"Xingyue Zhu, Die Xiao","doi":"10.1002/cpt.70084","DOIUrl":"https://doi.org/10.1002/cpt.70084","url":null,"abstract":"<p><p>Since 2016, the China National Medical Products Administration (NMPA) has reformed its drug registration classification rules and defines the innovative drugs as new drugs that have not been marketed domestically and overseas. This study sought to systematically evaluate the characteristics of the innovative drugs approved in China. The cross-sectional study included all innovative small molecules that submitted a marketing application after 2016 and were approved by the NMPA before 2024, as well as all innovative biologics and Chinese medicines that submitted after 2020 and were approved before 2024. Based on the NMPA's open databases, information on each drug and its pivotal trial was collected. A total of 167 innovative drugs were approved, consisting of 58.1% small molecules, 31.1% biologics, and 10.8% Chinese medicines. The domestic drugs dominated (86.8%) and continued to grow from 2018 to 2024. The drugs were concentrated in the oncology area (43.7%), particularly in biologics (55.8%). Most oncology drugs (90.4%) were approved based on surrogate end-point evidence. Chinese medicines received much less regulatory flexibility than small molecules/biologics. The expedited programs helped accelerate the clinical development and review processes. However, the review time tended to exceed the stipulated timeframes. The great efforts of the Chinese regulator and industry in nurturing innovation are bearing fruit. More investments from the regulator and drug developers are needed to focus on R&D in differentiated therapies, financial incentives and regulatory priorities for high-quality innovations, along with review capacity improvements, in order to facilitate an innovation-driven and internationally competent pharmaceutical industry in China.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273173","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":"Clinical Implementation of Pharmacogenomics and Drug-Drug Interaction Screening in a German Academic Teaching Hospital and Outpatient Follow-Up.","authors":"Roman Tremmel, Filippa Schreeck, Simon Jaeger, Severin Schricker, Elke Schaeffeler, Svitlana Igel, Daniela Steinberger, Manuel Pagitz, Jörg Latus, Markus Ketteler, Kerstin Bühl, Marc-H Dahlke, Hans-Georg Kopp, Matthias Schwab","doi":"10.1002/cpt.70083","DOIUrl":"https://doi.org/10.1002/cpt.70083","url":null,"abstract":"<p><p>Pharmacogenomics (PGx) helps to explain variability in drug response, including adverse drug reactions. Functional variants in genes affecting drug absorption, distribution, metabolism, and excretion (ADME) have been described. Despite PGx guidelines (e.g., CPIC and DPWG) enabling genotype-guided drug and dose selection, preemptive implementation remains challenging due to various issues including standardized result communication and integration into electronic health record (EHR) systems. We implemented PGx testing as well as drug-drug interaction (DDI) screening in a German academic hospital and assessed their impact on physicians, general practitioners (GPs), and patients. A novel PGx workflow was established using a 60-genetic variant panel. CPIC/DPWG guideline-based PGx reports were integrated into the EHR system and provided as a mobile and web application for patients through a genetic information system. Medication profiles and questionnaires evaluated PGx-based decisions 3 months post-discharge. Among 255 patients, 95% had at least one actionable PGx variant, most commonly affecting statins, 5-fluorouracil, irinotecan, and pantoprazole. Actionable recommendations were provided in 21.5%, with hospital physicians modifying treatment subsequently in 75.5%. We identified 57 clinically significant DDIs, including PGx drugs in 21%. GPs maintained optimized treatment in 77% of those patients with a medication change initiated during hospitalization. One in 10 patients discussed results with their GPs. GPs favored PGx for future prescriptions and requested training. We showed that preemptive PGx testing can be successfully implemented in a German hospital with high acceptance among physicians and GPs, and that PGx integration into the EHR supports broader adoption in precision medicine.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273099","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":"Dietary-Driven Gene Expansion.","authors":"Magnus Ingelman-Sundberg","doi":"10.1002/cpt.70092","DOIUrl":"https://doi.org/10.1002/cpt.70092","url":null,"abstract":"<p><p>Gene duplication has been shown to drive molecular evolution, with dietary pressures expanding detoxification genes across species. In humans, CYP2D6 gene duplications enhance alkaloid and drug metabolism, reflecting ancient dietary adaptations. Similarly, tobacco-feeding aphids amplify CYP6CY3 for nicotine and insecticide resistance, and as recently shown, woodrats expand several ADME genes for detoxifying creosote-rich diets. These examples of dietary-driven gene expansion (DGE) highlight diet's role in shaping genomic evolution, impacting drug responses and pesticide resistance.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273125","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":"Therapeutic Strategies of Denosumab Sequential Therapy: A Four-Armed Randomized Controlled Trial.","authors":"Hung-Kuan Yen, Chia-Che Lee, Chen-Yu Wang, Ta-Chun Lin, Shau-Huai Fu, Chuan-Ching Huang, Chih-Chien Hung, Olivier Q Groot, Chung-Yi Li","doi":"10.1002/cpt.70088","DOIUrl":"https://doi.org/10.1002/cpt.70088","url":null,"abstract":"<p><p>After denosumab discontinuation, the rebound effect can lead to rapid bone loss and increased fracture risk. Identifying effective sequential therapies after denosumab discontinuation is crucial to mitigate these risks. We conducted the Denosumab Sequential Therapy (DST) trial, a two-year, multicenter, open-label, randomized controlled trial, conducted at a referral center and two affiliated hospitals in Taiwan. The DST trial enrolled 101 patients aged 50 years or older who received denosumab for at least 2 years (median: 2 years) and stratified the patients into four intervention groups to evaluate the effectiveness of three therapeutic strategies compared to continuous denosumab treatment. The four arms were as follows: (1) continued denosumab for 2 years (denosumab group); (2) two consecutive annual zoledronate infusions (annual-zoledronate group); (3) one zoledronate infusion followed by a supervised medication-free year (biennial-zoledronate group); and (4) one zoledronate infusion followed by resumed denosumab (double-switching group). The primary outcome was the percent change in the lumbar spine (LS) bone mineral density (BMD), total hip BMD (TH-BMD), and femoral neck BMD (FN-BMD). Secondary outcomes included changes in BTMs, the incidence of clinical fractures, and the need for rescue zoledronate in the biennial-zoledronate group. LS-BMD increased by 1.77% in the denosumab group, by 2.25% in the double-switching group, while decreasing by 0.71% in the annual-zoledronate group and by 2.76% in the biennial-zoledronate group. One-third of patients in the biennial-zoledronate group showed LS-BMD loss exceeding the least significant change (LSC), and 22% required rescue zoledronate infusions. Given the significant bone loss observed, a single zoledronate infusion followed by a medication-free year is not recommended. Two consecutive zoledronate infusions and the double-switching regimen with resumed denosumab showed promising BMD preservation, making them advisable clinical alternatives after denosumab discontinuation.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243440","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":"Application of Physiologically Based Pharmacokinetic Modeling to Inform Dose Selection of Mezigdomide in a Phase I Drug-Drug Interaction Study.","authors":"Joseph Burnett, Caroline Sychterz, Jessica Katz, Faisal Shakeel, Jose Silva, Wencong Chen, Aditi Shahane, Xiaomin Wang, Manisha Lamba, Allison Gaudy","doi":"10.1002/cpt.70082","DOIUrl":"https://doi.org/10.1002/cpt.70082","url":null,"abstract":"<p><p>Mezigdomide (MEZI) is an oral, highly potent CELMoD™ agent with promising antitumor and immune-stimulatory activity, optimized for Aiolos and Ikaros degradation. Preclinical evidence suggests MEZI is primarily metabolized by cytochrome P450 (CYP) 3A4/5 and has the potential to inhibit efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. To predict the magnitude of enzyme- and transporter-mediated drug-drug interactions (DDI) and inform clinical study design, a physiologically based pharmacokinetic (PBPK) model was developed. A PBPK-informed Phase I clinical DDI study was conducted that evaluated MEZI as an object of CYP3A induction (rifampin) and inhibition (itraconazole) and as a precipitant of transporter-mediated interactions (digoxin and rosuvastatin). PBPK modeling predicted substantial interactions with strong and moderate CYP3A modulators, which informed a unique dose selection strategy, PK sampling time, and washout period. Clinical results confirmed reductions in MEZI exposure with rifampin (AUC reduced 93-95%) and increases with itraconazole (~14-fold for dose normalized AUC). MEZI was well-tolerated despite these changes in exposure. Additionally, coadministration of MEZI with P-gp and BCRP substrates, digoxin and rosuvastatin, showed no clinically meaningful changes in substrate plasma PK, indicating a low likelihood of significant transporter-mediated DDIs. The prospective PBPK model was refined with clinical data, improving predictions and supporting simulations for moderate/weak CYP3A modulators. This iterative \"learn-confirm\" approach underscores the utility of PBPK modeling in optimizing clinical trial design, ensuring participant safety, and anticipating DDI risks. The findings support MEZI's clinical development with informed dosing strategies, particularly for coadministration with CYP3A modulators.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243359","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 Pharmacokinetics and Exposure-Response Analyses of Momelotinib, Its Active Metabolite (M21), and Total Active Moiety in Myelofibrosis.","authors":"Benjamin Rich, Meenakshi Srinivasan, Yu Liu Ho, Sandra A G Visser, Geraldine Ferron-Brady, Georgios Vlasakakis","doi":"10.1002/cpt.70076","DOIUrl":"https://doi.org/10.1002/cpt.70076","url":null,"abstract":"<p><p>Momelotinib, a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor, is approved for the treatment of myelofibrosis with anemia. These analyses characterized the population pharmacokinetics of momelotinib and its active metabolite M21 following administration of the commercial tablet formulation in patients with myelofibrosis from phase II/III trials and other participants from phase I trials (N = 661). Predicted covariate effects on momelotinib, M21, and total active moiety (TAM)-representing the combined potency-weighted exposures of momelotinib and M21-exposures following 200-mg once-daily dosing were evaluated using a simulation-based approach. Using sequential modeling, momelotinib was described by a two-compartment model with six transit absorption compartments and first-order elimination, and M21 by a two-compartment model with first-order elimination. Hepatic function, concomitant CYP3A4 inducers, and concomitant OATP1B1/1B3 inhibitors were significant momelotinib covariates, while baseline creatinine clearance and hepatic function were significant M21 covariates, with cumulative effects on TAM. Exposure-response relationships between the average TAM concentration under actual dosing and key efficacy and safety end points were assessed using data from the 24-week randomized period of three phase III trials in patients with myelofibrosis (N = 417). After relevant covariate adjustment, significant positive relationships were identified with spleen volume reduction and transfusion independence (the latter specifically in JAK inhibitor-experienced patients), but not symptom improvement. Greater TAM exposure was significantly associated with lower odds of grade 3/4 anemia and higher odds of any-grade peripheral neuropathy, although the latter was infrequently observed in phase III trials. There was no significant relationship with grade ≥ 3 thrombocytopenia or any-grade diarrhea.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237430","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":"Drug Repositioning of Pegbing® for Essential Thrombocythemia: Insights from PK/PD Modeling and Extrapolation.","authors":"Weizhe Jian, Yalin Yin, Rong Chen, Junsheng Xue, Jianbo Gu, Zhengfang Du, Ruoyi He, Tianyan Zhou","doi":"10.1002/cpt.70079","DOIUrl":"https://doi.org/10.1002/cpt.70079","url":null,"abstract":"<p><p>Pegbing® (peginterferon alfa-2b), a pegylated interferon-alpha, is approved for the treatment of chronic hepatitis B (CHB) and C. One of its adverse effects is platelet (PLT) suppression. It is currently being repurposed for the treatment of essential thrombocythemia (ET), a rare myeloproliferative disorder characterized by abnormally elevated PLT levels and associated with significant unmet clinical needs. The drug repositioning strategy of Pegbing® from CHB to ET aims to accelerate development and reduce costs. Through the application of pharmacometrics, the existing data from CHB patients were leveraged to inform dose selection and clinical trial design for ET patients. The pharmacokinetic/pharmacodynamic (PK/PD) model of Pegbing® for PLT and white blood cell (WBC) inhibition was established using data from a phase II trial conducted in CHB patients who received Pegbing®, and validated with data from a phase III trial. The PK/PD relationship was extrapolated to ET patients by adjusting baseline PLT and WBC levels using real-world data from ET patients receiving off-label treatment with Pegbing®. According to the parameter distribution and correlation from the extrapolated PK/PD relationship, 1,000 virtual ET patients were generated to form an in silico clinical trial, revealing that baseline PLT and WBC levels were key factors for hematologic response. Pegbing® 180 μg is expected to be an appropriate dose for future development, with an overall complete hematologic response rate of 62.3%. A higher maintenance dose may be required in patients with severe ET. Moreover, this study provides a valuable reference for drug repositioning between two indications with significant differences.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231028","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":"Association Discovery Approach in Healthcare Big Data to Identify Drug Safety and Drug Repurposing Signals.","authors":"George S Q Tan, Lynn Miller, Sam Wade, Jenni Ilomäki, Dickson Lukose, Jia Rong, Geoffrey I Webb","doi":"10.1002/cpt.70080","DOIUrl":"https://doi.org/10.1002/cpt.70080","url":null,"abstract":"<p><p>Data science approaches have been increasingly implemented in healthcare big data to evaluate the safety and effectiveness of drugs. Association discovery is a data mining approach that finds potentially associated elements in high-dimensional data. We present a novel implementation of the association discovery approach in longitudinal healthcare data to identify drug safety and drug repurposing signals from positive and inverse associations between drug use and clinical outcomes, respectively. We used the 10% sample data from the Australian Pharmaceutical Benefits Scheme (2014-2024), which comprises prescription claims records. Using the Magnum Opus association discovery tool, we identified associations between a wide range of drugs and three common chronic medical conditions (i.e., coronary artery disease, type 2 diabetes, epilepsy). Cases with the conditions were identified using the supply of indicator drug(s) as a proxy for the conditions and matched to controls not supplied the indicator drug(s). Drug use was defined using Anatomical Therapeutic Chemical (ATC) codes supplied during a one-year lookback period before the supply of the indicator drug(s). We also evaluated combinations of up to four drugs and identified associations at the ATC level of drug class(es). In this study, we reproduced several known adverse drug events and protective drug effects, while some associations were attributable to confounding, mutual indications, or reverse causation. The remaining associations may represent previously uncharacterized drug safety and drug repurposing signals, necessitating further validation. We also discussed methodological differences between this association discovery approach and other similar data science approaches.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237436","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":"Regulatory Interactions and Learnings-RADIAL the Trials@Home Proof-of-Concept Trial on Decentralization.","authors":"Helga Gardarsdottir, Hamidou Traore, Kate Huntley, Dinesh Mistry, Amos J de Jong, Agnes Legathe, Tim de Smedt, Scott Askin, Megan Heath, Solange Corriol-Rohou, Bart Lagerwaard, Mira G P Zuidgeest","doi":"10.1002/cpt.70078","DOIUrl":"https://doi.org/10.1002/cpt.70078","url":null,"abstract":"<p><p>This paper is part of a series of six publications presenting lessons learned during the setup, regulatory submission, and conduct of the proof-of-concept Trials@Home RADIAL trial. The three-arm RADIAL trial, comprising fully decentralized, hybrid, and conventional arms, is the first clinical study to evaluate the feasibility and acceptability of decentralized clinical trial elements across six European countries. In this paper, insights from multiple formal regulatory interactions related to the RADIAL trial, conducted between 2021 and 2022, are presented. These interactions included (i) a consultation with the European Medicines Agency's Innovation Task Force, (ii) a national Scientific Advice procedure, and (iii) the clinical trial application submission under the EU Clinical Trials Regulation (Regulation EU 536/2014). Given the novelty of the decentralized approach and lack of guidelines, many constructive comments and questions were received that supported the finalization of the protocol and conduct of the trial. It is important to acknowledge that clinical trials often span multiple countries and regulatory jurisdictions, creating complexity due to variations in complementary national legal and regulatory requirements. We conclude that early and continuous regulatory engagement is essential for the successful implementation of innovative trial designs. Although progress has been made in supporting decentralized clinical trials, persistent challenges related to legislative heterogeneity remain. Harmonized regulatory guidance and greater transparency through the sharing of regulatory experiences will be key to facilitating the broader adoption of decentralized approaches and advancing clinical trials in Europe.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224786","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":"Perspective of the Pharmaceuticals and Medical Devices Agency on Drug Development for Childhood Myopia.","authors":"Mitsuru Arima, Motomasa Atsumi, Kumiko Takeuchi, Takumi Aoki, Emi Inagaki, Yosuke Kobayashi, Takuya Kageyama, Kazuki Izumi, Atsushi Yoshimura, Wataru Asakura","doi":"10.1002/cpt.70086","DOIUrl":"https://doi.org/10.1002/cpt.70086","url":null,"abstract":"<p><p>Pathologic myopia represents a global public health concern, with increasing prevalence and vision loss risk. Myopia typically develops in childhood and progresses more rapidly with earlier onset. Clinical trials exploring treatments for decelerating myopia progression are underway. In Japan, 0.025% atropine ophthalmic solution (RYJUSEA®) has been approved. This review outlines the evaluation process by the Pharmaceuticals and Medical Devices Agency (PMDA) and highlights challenges for future drug development.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211213","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}