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Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-18 Anna M. Mc Laughlin, Thomas Helland, Fenja Klima, Stijn L.W. Koolen, Ron H.N. van Schaik, Ron H.J. Mathijssen, Patrick Neven, Jesse J. Swen, Henk-Jan Guchelaar, Florence Dalenc, Melanie White-Koning, Robin Michelet, Gerd Mikus, Werner Schroth, Thomas Mürdter, Hiltrud Brauch, Matthias Schwab, Håvard Søiland, Gunnar Mellgren, Fabienne Thomas, Charlotte Kloft, Daniel L. Hertz
Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been
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Assessment of Dosing Strategies for Pediatric Drug Products Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-17 Zachary L. Taylor, Francis G. Green, Nayeem Hossain, Gilbert J. Burckart, Michael Pacanowski, Robert N. Schuck
Pediatric drug dosing is challenged by the heterogeneity of developing physiology and ethical considerations surrounding a vulnerable population. Often, pediatric drug dosing leverages findings from the adult population; however, recent regulatory efforts have motivated drug sponsors to pursue pediatric‐specific programs to meet an unmet medical need and improve pediatric drug labeling. This paradigm
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Genome‐Wide Association Study of Atorvastatin Pharmacokinetics: Associations With SLCO1B1, UGT1A3, and LPP Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-17 Anssi J.H. Mykkänen, E. Katriina Tarkiainen, Suvi Taskinen, Mikko Neuvonen, Maria Paile‐Hyvärinen, Tuomas O. Lilius, Tuija Tapaninen, Kathrin Klein, Matthias Schwab, Janne T. Backman, Aleksi Tornio, Mikko Niemi
In a genome‐wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration‐time curve from time zero to infinity (AUC0–∞) of atorvastatin (P = 1.2 × 10−10), 2‐hydroxy atorvastatin (P = 4.0 × 10−8), and 4‐hydroxy atorvastatin (P = 2.9 × 10−8). An intronic LPP variant, rs1975991
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Combination Therapy With Guselkumab and Golimumab in Patients With Moderately to Severely Active Ulcerative Colitis: Pharmacokinetics, Immunogenicity and Drug–Drug Interactions Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-16 Jie Shao, Marion Vetter, An Vermeulen, Brian G. Feagan, Bruce E. Sands, Julian Panés, Zhenhua Xu
A proof‐of‐concept study with the combination of guselkumab and golimumab in patients with ulcerative colitis (UC) has shown that the combination therapy resulted in greater efficacy than the individual monotherapies. The current analysis evaluated the pharmacokinetics (PK) and immunogenicity of guselkumab and golimumab in both the combination therapy and individual monotherapies. Blood samples were
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Artificial Intelligence and Disease Modeling: Focus on Neurological Disorders Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-14 Benjamin Ribba, Gennaro Pagano, Niklas Korsbo, Vijay Ivaturi, Antoine Soubret
CONFLICT OF INTEREST BR, GP, and AS are employees of F. Hoffmann-La Roche Ltd. All other authors declared no competing interests for this work. NK and NI are employees of PumasAI who are involved in the development of DeepNLME-based software.
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Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-14 Cheng Chen, Sean Hennessy, Colleen M. Brensinger, Todd A. Miano, Warren B. Bilker, Sascha Dublin, Sophie P. Chung, John R. Horn, Anika Tiwari, Charles E. Leonard
Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person‐time exposed to both an SMR and one of the three most dispensed
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Gene Polymorphisms of NLRP3 Associated With Plasma Levels of 4β‐Hydroxycholesterol, an Endogenous Marker of CYP3A Activity, in Patients With Asthma Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-14 Keita Hirai, Tomoki Kimura, Yuya Suzuki, Takayuki Shimoshikiryo, Toshihiro Shirai, Kunihiko Itoh
Inflammation decreases the activity of cytochrome P450 3A (CYP3A). Nucleotide‐binding oligomerization domain (NOD)‐like receptor family pyrin domain containing 3 (NLRP3) is responsible for regulating the inflammatory response, and its genetic polymorphisms have been linked to inflammatory diseases such as asthma. However, there have been few studies on the effect of NLRP3 on CYP3A activity. We aimed
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A Clinical Practice Perspective on the Evaluation of OATP1B1‐associated Drug Interactions Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-14 Céline K. Stäuble, Markus L. Lampert, Samuel S. Allemann, Henriette E. Meyer zu Schwabedissen
The liver uptake transporter OATP1B1 has been recognized by drug agencies as a determinant of drug–drug interactions. Nevertheless, labeling of OATP1B1 interactions appears limited considering available in vitro and in vivo data. This makes it difficult to evaluate OATP1B1-associated interactions in practice. Furthermore, genetic predisposition in SLCO1B1 (OATP1B1) affects systemic drug exposure and
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Chinese Expert Consensus on the Clinical Diagnosis and Management of Statin Intolerance Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-08 Jian-Jun Li, Ke-Fei Dou, Zhi-Guang Zhou, Dong Zhao, Ping Ye, Hong Chen, Zhen-Yue Chen, Dao-Quan Peng, Yuan-Lin Guo, Na-Qiong Wu, Jie Qian
The clinical benefits of statins have well-established and recognized worldwide. Although statins are well-tolerated generally, however, the report of statin-related adverse event and statin intolerance are common in China, which results in insufficient use of statins and poor adherence. The main reason may be attributed to confusions or misconceptions in the clinical diagnosis and management in China
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Algorithmic Identification of Treatment‐Emergent Adverse Events From Clinical Notes Using Large Language Models: A Pilot Study in Inflammatory Bowel Disease Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-09 Anna L. Silverman, Madhumita Sushil, Balu Bhasuran, Dana Ludwig, James Buchanan, Rebecca Racz, Mahalakshmi Parakala, Samer El‐Kamary, Ohenewaa Ahima, Artur Belov, Lauren Choi, Monisha Billings, Yan Li, Nadia Habal, Qi Liu, Jawahar Tiwari, Atul J. Butte, Vivek A. Rudrapatna
Outpatient clinical notes are a rich source of information regarding drug safety. However, data in these notes are currently underutilized for pharmacovigilance due to methodological limitations in text mining. Large language models (LLMs) like Bidirectional Encoder Representations from Transformers (BERT) have shown progress in a range of natural language processing tasks but have not yet been evaluated
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Impact of Treatment Modality and Route of Administration on Cytokine Release Syndrome in Relapsed or Refractory Multiple Myeloma: A Meta‐Analysis Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-09 Pooneh Soltantabar, Sheena Sharma, Diane Wang, Hoi‐Kei Lon, Akos Czibere, Anne Hickmann, Mohamed Elmeliegy
B‐cell maturation antigen (BCMA)‐targeting immunotherapies (e.g., chimeric antigen receptor T cells (CAR‐T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T‐cell activation and cytokine elevations leading to cytokine release syndrome
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A Randomized Crossover Trial of Mixed Meal Tolerance Test Response in People with Type 1 Diabetes on Insulin Pump Therapy and YG1699 or Dapagliflozin Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-08 Pablo Lapuerta, Silvia Urbina, Jiaojuan He, Alyssa Wittle, Chenghai Li, Tong Li, Helen Wang, Marcus Hompesch
YG1699 is a novel inhibitor of sodium‐glucose cotransporter 1 (SGLT1) and SGLT2. This double‐blind, 3‐way crossover trial compared YG1699 to dapagliflozin as an adjunct to insulin in people with type 1 diabetes (T1D) on insulin pump therapy. Treatment periods included four mixed meal tolerance tests (MMTTs) and insulin withdrawal tests per person. Nineteen adults with T1D were randomized to YG1699
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Clinical Pharmacology Perspective on Development of Adeno‐Associated Virus Vector‐Based Retina Gene Therapy Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-07 Jennifer Lynn Ford, Eleni Karatza, Hardik Mody, Prathap Nagaraja Shastri, Sana Khajeh Pour, Tong‐Yuan Yang, Michael Swanson, Daniel Chao, Damayanthi Devineni
Adeno‐associated virus (AAV) vector‐based gene therapy is an innovative modality being increasingly investigated to treat diseases by modifying or replacing defective genes or expressing therapeutic entities. With its unique anatomic and physiological characteristics, the eye constitutes a very attractive target for gene therapy. Specifically, the ocular space is easily accessible and is generally
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Dapagliflozin Reduces Urinary Kidney Injury Biomarkers in Chronic Kidney Disease Irrespective of Albuminuria Level Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-07 Junghyun Cho, Seung Whan Doo, Nayoung Song, Minsul Lee, Haekyung Lee, Hyongnae Kim, Jin Seok Jeon, Hyunjin Noh, Soon Hyo Kwon
The beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD) with low albuminuria levels have not been established. This study aimed to compare the effects of dapagliflozin on kidney injury biomarkers in patients with CKD stratified by albuminuria level. We prospectively enrolled healthy volunteers (HVs; n = 20) and patients with CKD (n =
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The US Food and Drug Administration's Model‐Informed Drug Development Meeting Program: From Pilot to Pathway Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-06 Rajanikanth Madabushi, Jessica Benjamin, Hao Zhu, Issam Zineh
CONFLICTS OF INTEREST The authors declared no competing interests for this work.
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How Much More Efficient Are Adaptive Platform Trials Than Multiple Stand‐Alone Trials? A Comprehensive Simulation Study for Streamlining Drug Development During a Pandemic Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-05 Masanao Sasaki, Hiroyuki Sato, Yukari Uemura, Ayako Mikami, Nao Ichihara, Shigeki Fujitani, Masashi Kondo, Yohei Doi, Eriko Morino, Daisuke Tokita, Norio Ohmagari, Wataru Sugiura, Akihiro Hirakawa
With the coronavirus disease 2019 (COVID‐19) pandemic, there is growing interest in utilizing adaptive platform clinical trials (APTs), in which multiple drugs are compared with a single common control group, such as a placebo or standard‐of‐care group. APTs evaluate several drugs for one disease and accept additions or exclusions of drugs as the trials progress; however, little is known about the
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A Randomized Trial Comparing Standard of Care to Bayesian Warfarin Dose Individualization Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-05 Ling Xue, Guangda Ma, Nick Holford, Qiong Qin, Yinglong Ding, Jacqueline A. Hannam, Xiaoliang Ding, Hongyou Fan, Zhenchun Ji, Biwen Yang, Han Shen, Zhenya Shen, Liyan Miao
The quality of warfarin treatment may be improved if management is guided by the use of models based upon pharmacokinetic‐pharmacodynamic theory. A prospective, two‐armed, single‐blind, randomized controlled trial compared management aided by a web‐based dose calculator (NextDose) with standard clinical care. Participants were 240 adults receiving warfarin therapy following cardiac surgery, followed
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Physiologically Based Pharmacokinetic Modeling to Investigate the Disease‐Drug–Drug Interactions between Voriconazole and Nirmatrelvir/Ritonavir in COVID‐19 Patients with CYP2C19 Phenotypes Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-02 Peile Wang, Shuaibing Liu, Jing Yang
Coronavirus disease 2019 (COVID‐19)‐associated pulmonary aspergillosis superinfection with cytokine storm is associated with increased mortality. This study aimed to establish a physiologically‐based pharmacokinetic (PK) model to investigate the disease‐drug–drug interactions between voriconazole and nirmatrelvir/ritonavir in patients with COVID‐19 with elevated interleukin‐6 (IL‐6) levels carrying
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The Impact of Regulatory Reforms in China on Drug Lag: The Role of Clinical Development Strategies Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-02 Yue Han, Rong Jiang, Jinlian Li, Yifei Wang, Rong Shao, Jinping Xie
In recent years, there has been significant focus on China's new drug lag, but relevant research is limited. This study explores the reasons for drug lag by assessing the impact of reforms in China's drug review system, particularly focusing on the influence of clinical development strategies. This study selected drugs first launched in the United States between 2017 and 2022, examining absolute and
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Genetic Determinants of Thiazide-Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances – A Genome-Wide Evaluation of the UK Biobank Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-29 Innocent G. Asiimwe, Lauren Walker, Reecha Sofat, Andrea L. Jorgensen, Munir Pirmohamed
Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide-use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6
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All that Glitters Is not Gold: Type‐I Error Controlled Variable Selection from Clinical Trial Data Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-29 Manuela R. Zimmermann, Mark Baillie, Matthias Kormaksson, David Ohlssen, Konstantinos Sechidis
Clinical trials are primarily conducted to estimate causal effects, but the data collected can also be invaluable for additional research, such as identifying prognostic measures of disease or biomarkers that predict treatment efficacy. However, these exploratory settings are prone to false discoveries (type‐I errors) due to the multiple comparisons they entail. Unfortunately, many methods fail to
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Asia‐Inclusive Global Development of Enpatoran: Results of an Ethno‐Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-28 Lena Klopp‐Schulze, Sathej Gopalakrishnan, Özkan Yalkinoglu, Yoshihiro Kuroki, Hong Lu, Kosalaram Goteti, Axel Krebs‐Brown, Marco Nogueira Filho, Ulrike Gradhand, Markus Fluck, Jamie Shaw, Jennifer Dong, Karthik Venkatakrishnan
Enpatoran is a novel, highly selective, and potent dual toll‐like receptor (TLR)7 and TLR8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. The ongoing phase II study (WILLOW; NCT05162586) is evaluating enpatoran for 24 weeks in patients with active SLE or CLE and is currently
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Dosing and Exposure of Vancomycin With Continuous Infusion: A Retrospective Study Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-27 Judith Y. M. N. Derijks‐Engwegen, Nynke G.L. Jager
Vancomycin continuous infusion (CI) has suggested benefits over intermittent infusion: reduced nephrotoxicity, higher target attainment, and simpler therapeutic drug monitoring (TDM). Empiric dosing regimens range from 30–60 mg/kg/day and it is unclear which regimen results in optimal exposure. This study evaluates whether a dosing regimen of 45 mg/kg/day after a 20 mg/kg loading dose for patients
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Mechanistic Determinants of Daprodustat Drug–Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B‐CYP2C8 Interplay Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-26 Yi‐An Bi, Samantha Jordan, Amanda King‐Ahmad, Mark A. West, Manthena V. S. Varma
Daprodustat is the first oral hypoxia‐inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B‐mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically‐based
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Impacts of Febuxostat on Cerebral and Cardiovascular Events in Elderly Patients with Hyperuricemia: Post Hoc Analysis of a Randomized Controlled Trial Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-23 Masahiro Sugawara, Sunao Kojima, Ichiro Hisatome, Kunihiko Matsui, Kazuaki Uchiyama, Naoto Yokota, Eiichi Tokutake, Yutaka Wakasa, Shinya Hiramitsu, Masako Waki, Hideaki Jinnouchi, Hirokazu Kakuda, Takahiro Hayashi, Naoki Kawai, Hisao Mori, Kenichi Tsujita, Yusuke Ohya, Kazuo Kimura, Yoshihiko Saito, Hisao Ogawa
A recent meta-analysis found no benefit of uric acid-lowering therapy including febuxostat on death, cardiovascular events, or renal impairment. However, there may be populations that benefit from febuxostat in reducing mortality and cerebral and cardiovascular events. The aim of the present study was to examine the clinical benefit of febuxostat in elderly patients stratified by age using Febuxostat
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How Do Risk Evaluation and Mitigation Strategies Impact Clinical Practice? A National Survey of Physicians Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-20 Ameet Sarpatwari, Zhigang Lu, Massimiliano Russo, Heidi Zakoul, Su Been Lee, Gita A. Toyserkani, Esther H. Zhou, Cynthia LaCivita, Katherine Hyatt Hawkins Shaw, Laura Zendel, Gerald J. Dal Pan, Aaron S. Kesselheim
The US Food and Drug Administration can require risk evaluation and mitigation strategy (REMS) programs for prescription drugs to ensure the benefits of use outweigh the risks. We conducted a national survey of physicians' experiences prescribing eight REMS-covered drugs: (1) ambrisentan; (2) bosentan; (3) clozapine; (4) isotretinoin; (5–7) the multiple myeloma (MM) drugs lenalidomide, pomalidomide
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A Score to Predict the Clinical Usefulness of Therapeutic Drug Monitoring: Application to Oral Molecular Targeted Therapies in Cancer Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-23 Arthur Géraud, David Combarel, Christian Funck‐Brentano, Quentin Beaulieu, Noël Zahr, Sophie Broutin, Jean‐Philippe Spano, Christophe Massard, Benjamin Besse, Paul Gougis
Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco‐hematology, TDM guidelines for oral molecular targeted therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identified key parameters for an oMTT's suitability for TDM
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Real‐World Evidence to Inform Regulatory Decision Making: A Scoping Review Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-23 Marieke S. Jansen, Olaf M. Dekkers, Saskia le Cessie, Lotty Hooft, Helga Gardarsdottir, Anthonius de Boer, Rolf H. H. Groenwold
Real‐world evidence (RWE) is increasingly considered in regulatory decision making. When, and to which extent, RWE is considered relevant by regulators likely depends on many factors. This review aimed to identify factors that make RWE necessary or desirable to inform regulatory decision making. A scoping review was conducted using literature databases (PubMed, Embase, Emcare, Web of Science, and Cochrane
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Impact of Drug Recalls on Patients in The Netherlands: A 5‐Year Retrospective Data Analysis Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-23 Pieter A. Annema, Hieronymus J. Derijks, Marcel L. Bouvy, Rob J. van Marum
Drug recalls occur frequently and have the potential to impact considerable numbers of patients and healthcare providers. However, in the absence of a comprehensive overview the extent of conducted recalls and their impact on patients remains unknown. To address this, we developed a comprehensive overview of drug recalls affecting patients. We compiled this overview based on the drug recall registrations
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Pharmacokinetic Enhancement of Elexacaftor/Tezacaftor/Ivacaftor for Cystic Fibrosis: A Cost Reduction Strategy to Address Global Disparities in Access Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-22 Eunjin Hong, Marco Zampoli, Paul M. Beringer
In this perspective, we highlight the significant global disparities encountered since the introduction of elexacaftor/tezacaftor/ivacaftor, which have largely excluded the cystic fibrosis population in low to middle income countries. We propose a pharmacokinetic (PK) enhancement strategy developed using physiologically-based pharmacokinetic (PBPK) modeling, to mitigate the high cost of treatment.
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The Efficacy, Effectiveness, and Efficiency of Integrated QTc Assessment: Rationalizing Approaches to New Drug Modalities Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-22 Matthew M. Abernathy, Derek J. Leishman
After nearly 3 decades of regulatory activity concerning new drugs' potential for delayed cardiac repolarization an integrated risk assessment paradigm for small molecule drugs has been established. Regulatory guidance also suggests that for large, targeted proteins and monoclonal antibodies no quantitative clinical QTc assessment is necessary. The expansion of new drug modalities prompts the question:
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A Generative and Causal Pharmacokinetic Model for Factor VIII in Hemophilia A: A Machine Learning Framework for Continuous Model Refinement Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-19 Alexander Janssen, Louk Smalbil, Frank C. Bennis, Marjon H. Cnossen, Ron A. A. Mathôt
In rare diseases, such as hemophilia A, the development of accurate population pharmacokinetic (PK) models is often hindered by the limited availability of data. Most PK models are specific to a single recombinant factor VIII (rFVIII) concentrate or measurement assay, and are generally unsuited for answering counterfactual (“what-if”) queries. Ideally, data from multiple hemophilia treatment centers
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Development and Validation of the Pharmacological Statin-Associated Muscle Symptoms Risk Stratification Score Using Electronic Health Record Data Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-19 Boguang Sun, Pui Ying Yew, Chih-Lin Chi, Meijia Song, Matt Loth, Yue Liang, Rui Zhang, Robert J. Straka
Statin-associated muscle symptoms (SAMS) can lead to statin nonadherence. This paper aims to develop a pharmacological SAMS risk stratification (PSAMS-RS) score using a previously developed PSAMS phenotyping algorithm that distinguishes objective vs. nocebo SAMS using electronic health record (EHR) data. Using our PSAMS phenotyping algorithm, SAMS cases and controls were identified from Minnesota Fairview
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Better Rejection-Free Survival at Three Years in Kidney Transplant Recipients With Model-Informed Precision Dosing of Mycophenolate Mofetil Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-19 Claire Villeneuve, Antoine Humeau, Caroline Monchaud, Marc Labriffe, Jean-phillipe Rerolle, Lionel Couzi, Pierre-François Westeel, Isabelle Etienne, Nassim Kamar, Mathias Büchler, Antoine Thierry, Pierre Marquet
The clinical impact of individual dose adjustment of mycophenolate mofetil is still debated, due to conflicting results from randomized clinical trials. This retrospective study aimed to compare 3-year rejection-free survival and adverse effects between adult kidney transplant recipients (KTRs) with or without mycophenolate mofetil model-informed precision dosing (MIPD). MIPD is defined here as mycophenolic
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Ticagrelor versus Adjusted-Dose Prasugrel in Acute Coronary Syndrome with Percutaneous Coronary Intervention Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-19 Ming-Lung Tsai, Yuan Lin, Dong-Yi Chen, Ming-Shyan Lin, Chao-Yung Wang, I-Chang Hsieh, Ning-I Yang, Ming-Jui Hung, Tien-Hsing Chen
Dual antiplatelet therapy (DAPT) with ticagrelor or adjusted-dose prasugrel has been used for acute coronary syndrome (ACS). However, few studies have directly compared these two drugs. In this study, we compared the real-world applications and outcomes of these two drugs in patients with ACS who had undergone percutaneous coronary intervention (PCI). This retrospective cohort study was conducted using
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Genetic Prediction of Smoking Cessation Medication Side Effects: A Genome-Wide Investigation of Abnormal Dreams on Varenicline Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-19 Meghan J. Chenoweth, Yong Jae Kim, Nikki L. Nollen, Larry W. Hawk, Martin C. Mahoney, Caryn Lerman, Jo Knight, Rachel F. Tyndale
Varenicline, the most efficacious smoking cessation monotherapy, produces abnormal dreams. Although genetic contributions to varenicline-associated nausea and cessation have been identified, the role of genetics in abnormal dreams is unknown. We conducted a genomewide association study (GWAS) of abnormal dreams in 188 European ancestry smokers treated with varenicline (NCT01314001). Additive genetic
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Pharmacokinetics, Pharmacodynamics, and Safety of Edoxaban in Pediatric Subjects: A Phase I Single-Dose Study Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-18 Peng Zou, Hamim Zahir, Anil Duggal, Grishma Pandya, James Jin, Tarek A. Leil
This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 to < 6 months (N = 12), 0.5 to < 2 years (N = 13), 2 to < 6 years (N = 13), 6 to < 12 years (N = 13)
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Scientific Review of the Proarrhythmic Risks of Oligonucleotide Therapeutics: Are Dedicated ICH S7B/E14 Studies Needed for Low-Risk Modalities? Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-16 Yusheng Qu, Kim A. Henderson, Tod A. Harper, Hugo M. Vargas
Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current
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Subcutaneous Biologics: Clinical Pharmacology and Drug Development Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-16 Sihem Ait-Oudhia, Joseph Chen, Junyi Li, Piet H. van der Graaf
Biologics are a therapeutic class of drugs derived from living organisms that have been used in medicine for thousands of years. It was in the 20th century that the formal recognition and distinction of biologics emerged, marked by the introduction of the term itself and the mass production of biological products such as vaccines and sera.1, 2 This period spurred efforts to standardize their definition
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Using Machine Learning to Determine a Suitable Patient Population for Anakinra for the Treatment of COVID-19 Under the Emergency Use Authorization Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-13 Qi Liu, Raj Nair, Ruihao Huang, Hao Zhu, Austin Anderson, Ozlem Belen, Van Tran, Rebecca Chiu, Karen Higgins, Jianmeng Chen, Lei He, Suresh Doddapaneni, Shiew-Mei Huang, Nikolay P. Nikolov, Issam Zineh
A randomized, double-blind, placebo-controlled study (SAVEMORE trial) provided data to support an Emergency Use Authorization (EUA) of anakinra in hospitalized adults with positive results of direct severe acute respiratory syndrome-coronavirus 2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely
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A Natural Language Processing Approach towards Harmonized Communication of Uncertainties Identified during the European Medicine Authorization Process Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-12 Stefan Verweij, Vincent Haverhoek, Erik Bergman, Gabriel Westman, Lourens T. Bloem
Within the European Union, the European Medicines Agency's (EMA's) European Public Assessment Report (EPAR) is an important source of information for healthcare professionals and patients that allows them to understand important risks and uncertainties associated with the use of a medicine. However, the EPAR sections describing such important uncertainties can differ substantially in wording, length
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Model-Based Prediction of Irinotecan-Induced Grade 4 Neutropenia in Cancer Patients: Influence of Incorporating Germline Genetic Factors in the Model Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-12 Spinel Karas, Ron H. J. Mathijssen, Ron H. N. van Schaik, Alan Forrest, Tim Wiltshire, Robert R. Bies, Federico Innocenti
Neutropenia is the major dose-limiting toxicity of irinotecan-based therapy. The objective of this study was to assess whether inclusion of germline genetic variants into a population pharmacokinetic/pharmacodynamic model can improve prediction of irinotecan-induced grade 4 neutropenia and identify novel variants of clinical value. A semimechanistic population pharmacokinetic/pharmacodynamic model
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Predictive Modeling of Drug-Related Adverse Events with Real-World Data: A Case Study of Linezolid Hematologic Outcomes Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-12 Anu Patel, Sarah B. Doernberg, Travis Zack, Atul J. Butte, Kendra K. Radtke
Electronic health records (EHRs) provide meaningful knowledge of drug-related adverse events (AEs) that are not captured in standard drug development and postmarketing surveillance. Using variables obtained from EHR data in the University of California San Francisco de-identified Clinical Data Warehouse, we aimed to evaluate the potential of machine learning to predict two hematological AEs, thrombocytopenia
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Beyond Population-Level Targets for Drug Concentrations: Precision Dosing Needs Individual-Level Targets that Include Superior Biomarkers of Drug Responses Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-08 Thomas M. Polasek, Richard W. Peck
The purpose of precision dosing is to increase the chances of therapeutic success in individual patients. This is achieved in practice by adjusting doses to reach precision dosing targets determined previously in relevant populations, ideally with robust supportive evidence showing improved clinical outcomes compared with standard dosing. But is this implicit assumption of translatable population-level
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Reinforcement Learning and PK-PD Models Integration to Personalize the Adaptive Dosing Protocol of Erdafitinib in Patients with Metastatic Urothelial Carcinoma Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-09 Alessandro De Carlo, Elena Maria Tosca, Martina Fantozzi, Paolo Magni
The integration of pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations with artificial intelligence/machine learning algorithms is one of the most attractive areas of the pharmacometric research. These hybrid techniques are currently under investigation to perform several tasks, among which precision dosing. In this scenario, this paper presents and evaluates a new framework embedding
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Tepid Uptake of Digital Health Technologies in Clinical Trials by Pharmaceutical and Medical Device Firms Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-02-02 Caroline Marra, Ariel D. Stern
Digital health technologies (DHTs) can enable more patient-centric therapeutic development by generating evidence that captures how patients feel and function, enabling decentralized trial designs that increase participant inclusivity and convenience, and collecting and structuring patient-generated data for regulators to use in approval decisions alongside traditional clinical outcomes. Although a
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Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL-17A (LY3509754): A Phase I Randomized Placebo-Controlled Study Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-31 Amita Datta-Mannan, Arie Regev, David E. Coutant, Andrew J. Dropsey, Joanne Foster, Spencer Jones, Josh Poorbaugh, Carsten Schmitz, Evan Wang, Michael E. Woodman
For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies. This first-in-human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL-17A target engagement profile of single or multiple oral doses of the small molecule IL-17A inhibitor
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Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: A Meta-Analysis and Meta-Regression Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-31 Ruud van der Veen, Marsh Königs, Simon Bakker, Andries van Iperen, Saskia Peerdeman, Pierre M. Bet, Jaap Oosterlaan
Cognitive impairments, common sequelae of acquired brain injury (ABI), significantly affect rehabilitation and quality of life. Currently, there is no solid evidence-base for pharmacotherapy to improve cognitive functioning after ABI, nevertheless off-label use is widely applied in clinical practice. This meta-analysis and meta-regression aims to quantitatively aggregate the available evidence for
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CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-29 Xiaoyu Men, Zachary L. Taylor, Victoria S. Marshe, Daniel M. Blumberger, Jordan F. Karp, James L. Kennedy, Eric J. Lenze, Charles F. Reynolds, Cristiana Stefan, Benoit H. Mulsant, Laura B. Ramsey, Daniel J. Müller
In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression
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A Retrospective Analysis of the Potential Impact of Differences in Aggregates on Clinical Immunogenicity of Biosimilars and their Reference Products Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-29 Cristina Fernandez-Mendivil, Niamh M. Kinsella, Hans C. Ebbers
Aggregates, in particular high molecular weight species (HMWs), have been linked to increased immunogenicity. The current understanding on the impact of HMWs is mainly based on in vitro and nonclinical studies and there are only limited data available associating differences in HMWs in marketed monoclonal antibodies (mAbs) to clinical outcomes. Biosimilars offer a unique opportunity to study the potential
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Concomitant Use of Sodium-Glucose Cotransporter 2 Inhibitors and Overactive Bladder Drugs and the Risk of Urinary Tract Infection Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-29 Sungho Bea, Hyesung Lee, Sohee Park, Young Min Cho, Won Suk Choi, Katsiaryna Bykov, Ju-Young Shin
Concomitant use of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and overactive bladder (OAB) drugs potentially poses a risk of urinary tract infections (UTIs) due to the urinary retention of highly concentrated glucose in the urine. Thus, this study aimed to investigate the risk of UTIs among patients who initiated SGLT-2i treatment while taking OAB drugs. This population-based cohort study
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Predicting Clinical Pharmacokinetics/Pharmacodynamics and Impact of Organ Impairment on siRNA-Based Therapeutics Using a Mechanistic Physiologically-Based Pharmacokinetic-Pharmacodynamic Model Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-28 Annie Lumen, Xinwen Zhang, Sandeep Dutta, Vijay V. Upreti
Approved and emerging siRNA therapeutics are primarily designed for targeted delivery to liver where the therapeutic gene silencing effects occurs. Impairment of hepatic/renal function and its impact on siRNA pharmacokinetics/pharmacodynamics (PKs/PDs) are yet to be mechanistically evaluated to describe the unanticipated clinical observations for this novel modality. We developed pathophysiologically
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Personalized Chronomodulated 5-Fluorouracil Treatment: A Physiologically-Based Pharmacokinetic Precision Dosing Approach for Optimizing Cancer Therapy Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-24 Fatima Zahra Marok, Jan-Georg Wojtyniak, Dominik Selzer, Robert Dallmann, Jesse J. Swen, Henk-Jan Guchelaar, Matthias Schwab, Thorsten Lehr
The discovery of circadian clock genes greatly amplified the study of diurnal variations impacting cancer therapy, transforming it into a rapidly growing field of research. Especially, use of chronomodulated treatment with 5-fluorouracil (5-FU) has gained significance. Studies indicate high interindividual variability (IIV) in diurnal variations in dihydropyrimidine dehydrogenase (DPD) activity – a
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Summary Report of a Public Workshop: Case Studies of Multi-Regional Clinical Trial Incorporating Concept of the ICH E17 Guideline Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-22 Nobuko Matsushima, Yasuto Otsubo, Yoko Aoi, Ryuta Nakamura, Shuhei Kaneko, Takashi Asakawa, Nobushige Matsuoka, Kei Watabe, Osamu Komiyama, Hideharu Yamamoto, Yuki Ando
To further our understanding of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline and promote effective implementation, a public workshop was held in Japan by regulatory agency and industry representatives. In this workshop, important concepts explained in the ICH E17 guideline, such as intrinsic/extrinsic ethnic factors that
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Relationships of Proton Pump Inhibitor-Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-22 Rika Fukui, Satoshi Noda, Yoshito Ikeda, Yuichi Sawayama, Tomohiro Terada, Yoshihisa Nakagawa, Shin-ya Morita
Proton pump inhibitors (PPIs) have recently been reported to be linked with nephrotoxicity. PPIs are metabolized mainly or partly by cytochrome P450 2C19 (CYP2C19). However, the relationship between CYP2C19 genetic polymorphism and PPI-induced nephrotoxicity is unclear. In this study, we aimed to analyze the association between the time of occurrence of renal injury by PPIs, including lansoprazole
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Population Pharmacokinetics of Pediatric Lopinavir/Ritonavir Oral Pellets in Children Living with HIV in Africa Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-21 Suthunya Chupradit, Dalton C. Wamalwa, Elizabeth Maleche-Obimbo, Adeodata R. Kekitiinwa, Juliet Mwanga-Amumpaire, Elizabeth A. Bukusi, Winstone M. Nyandiko, Joseph K. Mbuthia, Alistair Swanson, , Tim R. Cressey, Baralee Punyawudho, Victor Musiime
Antiretroviral therapy for children living with HIV (CLHIV) under 3 years of age commonly includes lopinavir/ritonavir (LPV/r). However, the original liquid LPV/r formulation has taste and cold storage difficulties. To address these challenges, LPV/r oral pellets have been developed. These pellets can be mixed with milk or food for administration and do not require refrigeration. We developed the population
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Progress in Clinical Pharmacology in China: A Randomized Controlled Study to Advance Genotype-Guided Precision Medicine Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-22 Liang Zhao, Kathleen M. Giacomini, Piet H. van der Graaf
Currently, genotype-guided dosing strategies are gaining increased attention in precision medicine. The approach involves tailoring medication doses based on an individual's genetic makeup to optimize treatment outcomes and minimize adverse effects. Genetic factors that modulate drug response typically include polymorphisms in drug metabolizing enzymes that affect drug exposure, and dose adjustments
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Clinical Pharmacology Approaches to Support Approval of New Routes of Administration for Therapeutic Proteins Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-18 Yow-Ming C. Wang, Ping Ji, Sudharshan Hariharan, Jie Wang, Olanrewaju Okusanya, Bilal AbuAsal, Hao Zhu, Rajanikanth Madabushi, Shiew Mei Huang, Issam Zineh
Intravenous or subcutaneous routes of administration (ROAs) are common dosing routes for therapeutic proteins. Eleven therapeutic proteins with approval for one ROA have subsequently received approval for a second ROA. The clinical programs supporting the second ROA consistently leveraged data from the first ROA and included studies that characterized the pharmacokinetics (PKs) of the drug administered
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Model-Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-16 Peter N. Morcos, Jonathan Moss, Josh Veasy, Florian Hiemeyer, Barrett H. Childs, Dirk Garmann
Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefit–risk profile of the class PI3K inhibitors were scrutinized for use
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Quantitative Model-Based Assessment of Multiple Sickle Cell Disease Therapeutic Approaches Alone and in Combination Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-01-16 Amy T. Moody, Jatin Narula, Tristan S. Maurer
Three sickle cell disease (SCD) treatment strategies, stabilizing oxygenated hemoglobin (oxyHb), lowering 2,3-BPG, and inducing fetal hemoglobin (HbF) expression aim to prevent red blood cell (RBC) sickling by reducing tense-state sickle hemoglobin that contributes to polymer formation. Induction of 30% HbF is seen as the gold standard because 30% endogenous expression is associated with a lack of