Clinical Pharmacology & Therapeutics最新文献

{"title":"Current Use of Physiologically-Based Pharmacokinetic (PBPK) Modeling in New Medicinal Product Approvals at EMA: A Clinical Appraisal of Voclosporin in Lupus Nephritis.","authors":"Dirk R J Kuypers","doi":"10.1002/cpt.3737","DOIUrl":"https://doi.org/10.1002/cpt.3737","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172405","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":"Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment.","authors":"Nikki de Rouw, Leila-Sophie Otten, Mart P Kicken, Berber Piet, Bonne Biesma, Bianca van Veggel, Christi M J Steendam, Ben van den Borne, Lizza E L Hendriks, Sander Croes, Anne-Marie C Dingemans, Daphne W Dumoulin, Ron H J Mathijssen, Jacobus A Burgers, Alwin D R Huitema, Hieronymus J Derijks, Maarten J Deenen, Michel M van den Heuvel, Rob Ter Heine","doi":"10.1002/cpt.3735","DOIUrl":"https://doi.org/10.1002/cpt.3735","url":null,"abstract":"<p><p>Pemetrexed is a cornerstone in chemo(immunotherapy) of non-small cell lung cancer and mesothelioma; however, it is contraindicated in patients with renal impairment due to severe toxicity concerns. Therefore, a large proportion of patients is withheld from effective chemo(immunotherapy). We performed an intra-patient 3 + 3 dose escalation renal impairment study (eGFR < 45 mL/min). The pemetrexed dose was calculated based on renal function to reach a target AUC, and patients received oral folinic acid prophylaxis 45 mg four times daily on Days 2-15 of each cycle. Endpoints included safety (incidence of hematological and non-hematological toxicity, treatment delays) and pharmacokinetics in line with regulatory guidance for renal impairment trials. Six patients with an estimated glomerular filtration rate (eGFR) between 26 and 41 mL/min were included. All patients were successfully escalated to the full dose. Adverse event patterns and pharmacokinetics were comparable to those in patients with normal renal function. Grade I/II anemia occurred in five patients (already present at baseline). One occurrence of grade IV neutropenia was observed, which resolved without intervention. Moreover, in three patients, a 1-week treatment delay occurred. Treatment resulted in a response in four patients (n = 1 complete response, n = 2 partial response, n = 1 stable disease). Pemetrexed can be safely administered in patients with impaired renal function when the dose is calculated based on renal function and folinic acid prophylaxis is administered, thereby enabling an effective treatment modality for patients that, thus far, could not be treated.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148740","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":"Predicting OCT2/MATEs-Mediated Drug Interactions in Healthy Volunteers and Patients with Chronic Kidney Disease: Insights from Extended Clearance Concept, Endogenous Biomarkers, and In Vitro Inhibition Studies (Perspectives from the International Transporter Consortium).","authors":"Satoshi Asano, Aleksandra Galetin, Yoshiko Tomita, Kathleen M Giacomini, Xiaoyan Chu, Xinning Yang, Toshimichi Nakamura, Hiroyuki Kusuhara, Yuichi Sugiyama","doi":"10.1002/cpt.3727","DOIUrl":"https://doi.org/10.1002/cpt.3727","url":null,"abstract":"<p><p>Organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) transporters play significant roles in the renal secretion of organic cations and drug-drug interactions (DDIs). Recent in vitro studies indicate that the K_i values for OCT2 exhibit substrate dependency and increase in potency with pre-incubation. However, consensus is lacking on whether these factors should be considered in predicting in vivo inhibition. Physiologically based pharmacokinetic models, combined with the extended clearance concept, have been used and are discussed here for OCT2/MATEs probes. In addition to modeling, early clinical studies use endogenous biomarkers to evaluate transporter-mediated DDI risk, with the aim of avoiding unnecessary clinical DDI studies. Identified biomarkers for OCT2/MATEs, such as creatinine, N¹-methylnicotinamide, and N¹-methyladenosine, have proven useful in confirming clinically relevant OCT2/MATEs-mediated DDIs when renal clearance (CLr) is used as an endpoint; their application is discussed further. From a clinical perspective, the intact nephron hypothesis (INH), which postulates that the decrease in CLr in chronic kidney disease (CKD) is proportional to that in nephron numbers, has been proposed. However, reports suggest that the secretion clearance of creatinine and substrates of organic anion transporters (OATs) does not follow this proportionality in patients with CKD. This state-of-the-art review highlights key developments in predicting OCT2/MATEs-mediated DDIs in healthy volunteers and explores the prediction of clinical OCT2/MATEs DDI risk in patients with CKD by comparing substrate-dependent changes in secretion clearance for substrates of OCT2/MATEs and OATs. Recommendations for the prediction of OCT2/MATEs-mediated DDI risk, together with the current knowledge gaps and future directions, are discussed.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148741","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":"An Integrated AI-PBPK Platform for Predicting Drug In Vivo Fate and Tissue Distribution in Human and Inter-Species Extrapolation.","authors":"Wei Wang, Nannan Wang, Yiyang Wu, Zhuyifan Ye, Liang Zhao, Xianfeng Chen, Defang Ouyang","doi":"10.1002/cpt.3732","DOIUrl":"https://doi.org/10.1002/cpt.3732","url":null,"abstract":"<p><p>Optimal pharmacokinetic (PK) profile, including tissue distribution, is pivotal for a drug achieving success in clinical trials. Traditionally, PK estimation in early drug development has relied on extensive in vitro and in vivo testing to assess drug-like properties, a process that is not only costly and time-consuming but also limited in its ability to evaluate the synergistic effects of multiple properties. This study aims to develop an integrated artificial intelligence (AI) and physiologically based pharmacokinetic (PBPK) platform to rapidly estimate drug in vivo fate based solely on molecular structures. The AI models were trained to predict eight types of key properties (solubility, pKa values, crystal density, intrinsic dissolution rate, apparent permeability, protein unbound fraction, plasma clearance, and tissue partition coefficients for 15 organs), from which the PBPK model forecasted PK curves without further training. The AI-PBPK approach was validated against human PK data of 71 intravenous and 606 oral administrations collected from the PK-DB database. The results were robust, with most of the AUC predictions falling within two and threefold error ranges. The AI-PBPK model also accurately predicted drug organ selectivity, and for drugs exhibiting high plasma clearance, predictions were optimized through an inter-species extrapolation approach. This study illustrates that the developed modeling strategy adeptly addresses pivotal PK challenges in drug discovery and aligns with contemporary drug development processes. The modeling system can guide candidate selection, advancing more drugs with favorable PK profiles into clinical trials, thereby significantly enhancing the efficiency of drug development.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148739","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":"Absolute Oral Bioavailability and Bioequivalence of LSD Base and Tartrate in a Double-Blind, Placebo-Controlled, Crossover Study.","authors":"Denis Arikci, Friederike Holze, Lorenz Mueller, Patrick Vizeli, Deborah Rudin, Dino Luethi, Cedric M Hysek, Matthias E Liechti","doi":"10.1002/cpt.3726","DOIUrl":"https://doi.org/10.1002/cpt.3726","url":null,"abstract":"<p><p>Lysergic acid diethylamide (LSD) is currently being investigated as a potential treatment for psychiatric and neurological disorders. Different LSD formulations (base or tartrate, oral or intravenous) are being used. Unclear is whether LSD base and tartrate pharmacokinetics are equivalent. Additionally, LSD's absolute oral bioavailability is unknown. Therefore, we tested the bioequivalence of different oral LSD base and tartrate formulations and defined LSD's absolute oral bioavailability at a dose of ~80 μg freebase equivalent. We used a randomized, double-blind, placebo-controlled, five-period crossover design in 20 healthy participants to investigate an ethanolic drinking solution of LSD base, a watery drinking solution of LSD tartrate, a rapid dissolvable tablet of LSD base, an intravenous formulation of LSD tartrate, and corresponding placebos. We assessed pharmacokinetic parameters and acute subjective, autonomic, and adverse effects up to 24 hours. All oral formulations were bioequivalent, with the ethanolic base solution as a reference. The area under the concentration-time curve from zero to infinity and maximum plasma concentration were within a 90% confidence interval of 80-125%. The absolute bioavailability of oral LSD was 80% and similar for all tested formulations. Overall, the oral formulations showed comparable pharmacokinetic and pharmacodynamic parameters. Intravenous LSD administration produced higher \"any drug effect,\" \"good drug effect,\" and \"ego dissolution\" compared with oral LSD tartrate, more \"anxiety\" compared with all oral formulations, and more \"nausea\" and \"bad drug effect\" compared with oral LSD base and tartrate. In conclusion, dosing with LSD base and tartrate can be considered bioequivalent with high and similar oral bioavailability.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141367","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":"Caution with PBPK Modeling Based on the In Vitro Kinetics for Bilirubin Hepatic Uptake and Glucuronidation: Commentary on Dong et al.","authors":"John O Miners, Thomas M Polasek","doi":"10.1002/cpt.3734","DOIUrl":"https://doi.org/10.1002/cpt.3734","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141368","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":"Convergence of Several Biorhythms in Immunosuppressive Therapy for Liver Transplantation: Commentary on Ushijima et al.","authors":"William J Jusko","doi":"10.1002/cpt.3723","DOIUrl":"https://doi.org/10.1002/cpt.3723","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141369","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":"From Discovery to Translation: Endogenous Substrates of OAT1 and OAT3 as Clinical Biomarkers for Renal Secretory Function.","authors":"Aarzoo Thakur, Dilip K Singh, Katherine D Hart, Emese Kis, Zsuzsanna Gáborik, Travis T Denton, John D Clarke, Mary F Paine, Bhagwat Prasad","doi":"10.1002/cpt.3719","DOIUrl":"10.1002/cpt.3719","url":null,"abstract":"<p><p>The recent ICH M12 guidance on Drug Interaction Studies encourages the use of alternate approaches for predicting drug-drug interaction (DDI) potential of new chemical entities. One approach involves the use of endogenous substrates of drug metabolizing enzymes and transporters (DMET) as biomarkers, which can assess the inhibitory potential of new chemical entities towards DMET during Phase 1 clinical studies. Thus, biomarkers could potentially eliminate the need for dedicated DDI studies with exogenous probe substrates. Metabolomics, in conjunction with in vitro and/or in vivo preclinical models or clinical studies, can be used for biomarker discovery. We developed and applied a novel metabolomics-based DMET biomarker discovery (MDBD) approach to identify and qualify biomarkers of renal organic anion transporter 1 (OAT1) and OAT3. Untargeted metabolomics of pooled plasma and urine samples (n = 16) from a pharmacokinetic DDI study using the OAT1/3 inhibitor, probenecid, yielded 153 features identified as putative OAT1/3 biomarkers. Subsequently, in vitro transporter uptake assays using processed urine samples confirmed 57 of these features as OAT1 and/or OAT3 substrates. Finally, 23 features were clinically validated as OAT1/3 biomarkers through a detailed pharmacokinetic analysis (0-24 h) of plasma and urine samples (n = 4). These biomarkers, either alone or as part of a panel, can predict OAT1/3-mediated DDIs and interindividual variability in the renal secretory clearance of organic anions across different populations, thereby enabling translational utility in clinical settings. The novel MDBD approach can be extended to discover biomarkers of enzymes and other transporters.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118461","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 Interactions Brewing.","authors":"Matthijs W van Hoogdalem, Kathleen M Giacomini","doi":"10.1002/cpt.3709","DOIUrl":"https://doi.org/10.1002/cpt.3709","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101271","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":"Dose Optimization in Oncology Drug Development: Risk Factors for Postmarketing Requirements and Commitments.","authors":"Hiroe Kitagaki, Kentaro Takeda, Kazuya Murai, Hideki Maeda","doi":"10.1002/cpt.3722","DOIUrl":"https://doi.org/10.1002/cpt.3722","url":null,"abstract":"<p><p>Optimal dosing of oncological drugs is historically determined based on the \"higher is better\" paradigm. However, a paradigm shift in optimal dose selection has occurred in the development of new modalities, including molecularly targeted drugs, antibody drugs, and immunotherapies. In 2021, Project Optimus was launched by the Food and Drug Administration Oncology Center of Excellence to reform the dose optimization and dose selection paradigm in oncology drug development. In August 2024, \"Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases\" was published, encouraging randomized evaluation of the benefit/risk profile of a range of doses before initiating a registration trial. Although Project Optimus offers general guidance on dose optimization, it does not specify which early clinical data requires a more cautious approach to dose optimization. This is the first comprehensive study to investigate newly approved oncology drugs by the FDA over a long period and to identify the risk factors for postmarketing requirement or commitment to dose optimization, using logistic regression analysis. Our findings show that when the labeled dose is the maximum tolerated dose, the percentage of adverse reactions leading to treatment discontinuation is increased, and an exposure-safety relationship is established, the risk for postmarketing requirement or commitment to dose optimization is increased. Our study will provide actionable, data-driven insights into dose optimization strategies by objectively and quantitatively evaluating risk factors. These findings will serve as valuable guidance for designing more effective early-phase trials, complementing the FDA Project Optimus guidance.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109267","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}