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Application and Quality of Model‐Based Meta‐Analysis in Pharmaceutical Research: A Systematic Cross‐Sectional Analysis and Practical Considerations Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-10 Zhirong Yang, Hua He, Rui Wang, Dongyang Liu, Ge Li, Feng Sun
Model‐based meta‐analysis (MBMA) can be used in assisting drug development and optimizing treatment in clinical practice, potentially reducing costs and accelerating drug approval. We aimed to assess the application and quality of MBMA studies. We searched multiple databases to identify MBMA in pharmaceutical research. Eligible MBMA should incorporate pharmacological concepts to construct mathematical
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Questioning Conclusions and Statements on the German HTA System: A Critical Perspective Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-09 Jörg Tomeczkowski, Tanja Heidbrede, Friedhelm Leverkus, Sarah Schmitter, Charalabos‐Markos Dintsios, Ulrike Osowski, Kirsten H. Herrmann, Tobias Bluhmki, Almuth Marx, Birte Eichinger, Edin Basic, Paul Bussilliat, Eva Susanne Dietrich
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Model‐Informed Precision Dosing Using Machine Learning for Levothyroxine in General Practice: Development, Validation and Clinical Simulation Trial Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-07 Jules M. Janssen Daalen, Djoeke Doesburg, Liesbeth Hunik, Rogier Kessel, Thomas Herngreen, Dennis Knol, Thony Ruys, Bart J.F. van den Bemt, Henk J. Schers
Levothyroxine is one of the most prescribed drugs in the western world. Dosing is challenging due to high‐interindividual differences in effective dosage and the narrow therapeutic window. Model‐informed precision dosing (MIPD) using machine learning could assist general practitioners (GPs), but no such models exist for primary care. Furthermore, introduction of decision‐support algorithms in healthcare
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Sex and the Kidney Drug‐Metabolizing Enzymes and Transporters: Are Preclinical Drug Disposition Data Translatable to Humans? Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-07 Aarzoo Thakur, Guihua Yue, Deepak Ahire, Vijaya S. Mettu, Abrar Al Maghribi, Kaitlyn Ford, Lucia Peixoto, J. Steven Leeder, Bhagwat Prasad
Cross‐species differences in drug transport and metabolism are linked to poor translation of preclinical pharmacokinetic and toxicology data to humans, often resulting in the failure of new chemical entities (NCEs) during clinical drug development. Specifically, inaccurate prediction of renal clearance and renal accumulation of NCEs due to differential abundance of enzymes and transporters in kidneys
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Transcriptomic Profiles Associated with Experimental Placebo Effects in Chronic Pain Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-07 Luana Colloca, Evelina Mocci, Yang Wang, Rachel Massalee, Shuo Chen, Jewel White, Kesha Johnson, Gloria M. Patron Fidalgo, Gerald M. Wilson, David Goldman, Susan G. Dorsey
Gene expression networks associated with placebo effects are understudied; in this study, we identified transcriptomic profiles associated with placebo responsivity. Participants suffering from chronic pain underwent a verbal suggestion and conditioning paradigm with individually tailored thermal painful stimulations to elicit conditioned placebo effects. Participants reported pain intensity on a visual
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Results from a Joined Prospective Study to Evaluate the Sensitivity of the In Vivo Dog QT Assay in Line with the ICH E14/S7B Q&A Best Practices Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-06 Anne‐Marie Bétat, Annie Delaunois, Eric Delpy, Mathilde Loiseau, Anne Maurin, Gwendoline Poizat, Celine Possémé, Ferdinand Weinelt, Christophe Drieu la Rochelle, Eric Martel, Jean‐Pierre Valentin
The ICH E14/S7B Q&As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the in vivo non‐rodent QT assay as a component of the integrated risk assessment to potentially support a TQT waiver or substitute. We conducted a dog telemetry study to assess the effects on QTc of six reference compounds (five positive and one negative) previously
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Transforming the Discovery of Targeted Protein Degraders: The Translational Power of Predictive PK/PD Modeling Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-06 Robin Thomas Ulrich Haid, Andreas Reichel
Targeted protein degraders (TPDs), an emerging therapeutic modality, are attracting considerable interest with the promise to address disease‐related proteins that are not druggable with conventional small molecule inhibitors. Despite their novel mechanism of action, the PK/PD relationship of degraders is still approached with a mindset deeply rooted in inhibitor drugs. Here, we establish how predictive
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Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-03 Robert M. Lester, Caroline Engel, Aernout D. van Haarst, Sabina Paglialunga
Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction
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Approval of Mycophenolate Mofetil for Prophylaxis of Organ Rejection in Pediatric Recipients of Heart or Liver Transplants: A Regulatory Perspective Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-05-02 Amer Al‐Khouja, Nadia Chaudhri, Ergun Velidedeoglu, Ozlem Belen, Youwei Bi, Suresh Doddapaneni, Jianmeng Chen
On June 6, 2022, the FDA expanded the indications for mycophenolate mofetil (MMF) to include the prophylaxis of organ rejection in combination with other immunosuppressants in pediatric recipients of allogeneic heart or liver transplants aged 3 months and older. The approved oral dosing regimen for these patients was a starting dose of 600 mg/m2 with titration up to a maximum of 900 mg/m2 twice daily
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Zibotentan Can Be Co‐administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug–Drug Interaction Study Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-30 Anne‐Kristina Mercier, Abigail K. Kois, Deeyen Karsanji, Richard Baldry, Filip Birve, Maria Hedwall, Oleksandr Molodetskyi, Michael Gillen
The endothelin A receptor antagonist zibotentan, combined with the sodium‐glucose co‐transporter‐2 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided.
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From Dose to Exposure: Shifting the Paradigm of Pediatric Clinical Pharmacology Research and Education Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-30 Ronaldo Morales Junior, Victor Amajor, Kelli Paice, Kathryn E. Kyler, H. Rhodes Hambrick, Kathryn E. Pavia, Andrew S. Haynes, Felicia Gooden, Gwendolyn M. Pais, Kevin J. Downes, Laura B. Ramsey, Jonathan Wagner, Sonya Tang Girdwood
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Dose Optimization Informed by PBPK Modeling: State‐of‐the Art and Future Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-30 Karen Rowland Yeo, Eva Gil Berglund, Yuan Chen
Model‐informed drug development (MIDD) is a powerful quantitative approach that plays an integral role in drug development and regulatory review. While applied throughout the life cycle of the development of new drugs, a key application of MIDD is to inform clinical trial design including dose selection and optimization. To date, physiologically‐based pharmacokinetic (PBPK) modeling, an established
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Optimal Treatment Based on Interferon No Longer Makes Clinical Cure of Chronic Hepatitis B Far Away: An Evidence‐Based Review on Emerging Clinical Data Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-30 Yujing Li, Fada Wang, Jing Zhou, Lanqing Li, Chengrun Song, Enqiang Chen
Chronic hepatitis B (CHB) remains a major global public health problem. The functional cure is the ideal therapeutic target recommended by the latest guidelines, and pursuing a functional cure has become the key treatment end point of current therapy and for upcoming clinical trials. In this review, based on the latest published clinical research evidence, we analyzed the concept and connotation of
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“Getting the Dose Right”—Revisiting the Topic With Focus on Biologic Agents Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-29 Diane R. Mould, Richard N. Upton
Nearly two decades after the Peck and Cross article ‘“Getting the dose right: facts, a blueprint, and encouragements” was published, a review of dose recommendations for biologics shows that the success in getting the dose right appears to have improved given the relatively low incidence of drug withdrawals and dosing/label changes. However, the clinical experience with monoclonal antibodies (MAbs)
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The Evolution of Drug Regulatory Sciences in the Netherlands: More than a Country Report Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-29 Anna M. G. Pasmooij, Peter G. M. Mol, Jacob Cornelis Bot, Hubert G. M. Leufkens
In the Netherlands, drug regulatory science is a vibrant national and internationally oriented community. In this review, we present the factors that have contributed to this successful collaboration between relevant stakeholders and that led to a surge of activities around how regulatory science became embedded in the ecosystem of medicines research, clinical pharmacology, policymaking and regulation
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Viral Kinetics Model of SARS‐CoV‐2 Infection Informs Drug Discovery, Clinical Dose, and Regimen Selection Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-27 Allison M. Claas, Meelim Lee, Pai‐Hsi Huang, Charles G. Knutson, Domenico Bullara, Birgit Schoeberl, Suzanne Gaudet
Quantitative systems pharmacology (QSP) has been an important tool to project safety and efficacy of novel or repurposed therapies for the SARS‐CoV‐2 virus. Here, we present a QSP modeling framework to predict response to antiviral therapeutics with three mechanisms of action (MoA): cell entry inhibitors, anti‐replicatives, and neutralizing biologics. We parameterized three distinct model structures
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Evaluation of Patient‐Centric Sample Collection Technologies for Pharmacokinetic Assessment of Large and Small Molecules Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-27 Sandhya Mandlekar, Dhruvitkumar S. Sutaria, Xiaoyun Yang, Ryan Johnson, Yixuan Zou, Brian Dean, Liuxi Chen, Rucha Sane, Kathi Williams, Alison Cardenas, Mary Simon, Saloumeh Fischer
Low‐volume sampling devices offer the promise of lower discomfort and greater convenience for patients, potentially reducing patient burden and enabling decentralized clinical trials. In this study, we determined whether low‐volume sampling devices produce pharmacokinetic (PK) data comparable to conventional venipuncture for a diverse set of monoclonal antibodies (mAbs) and small molecules. We adopted
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B‐ and T‐Lymphocyte Attenuator in Systemic Lupus Erythematosus Disease Pathogenesis Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-27 Andrew C. Vendel, Lukasz Jaroszewski, Matthew D. Linnik, Adam Godzik
B‐ and T‐lymphocyte attenuator (BTLA; CD272) is an immunoglobulin superfamily member and part of a family of checkpoint inhibitory receptors that negatively regulate immune cell activation. The natural ligand for BTLA is herpes virus entry mediator (HVEM; TNFRSF14), and binding of HVEM to BTLA leads to attenuation of lymphocyte activation. In this study, we evaluated the role of BTLA and HVEM expression
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Efficacy and Safety of Fibroblast Growth Factor‐21 Analogs for the Treatment of Metabolic Dysfunction‐Associated Steatohepatitis: A Systematic Review and Meta‐Analysis Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-26 Changhyeon Jeong, Nayoung Han, Nakyung Jeon, Su‐jin Rhee, Christine E. Staatz, Min‐Soo Kim, In‐hwan Baek
Fibroblast growth factor (FGF)‐21 analogs are potential therapeutic candidates for metabolic dysfunction‐associated steatohepatitis (MASH). This systematic review and meta‐analysis aimed to assess the efficacy and safety of the FGF‐21 analogs, efruxifermin, pegbelfermin, and pegozafermin for MASH treatment. A comprehensive systematic review and meta‐analysis of randomized controlled trials from five
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How PBPK Can Help to Understand Old Drugs and Inform their Dosing in Elderly: Amantadine Case Study Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-26 Olha Shuklinova, Sibylle Neuhoff, Sebastian Polak
Amantadine, despite being on the market for 55 years, has several unknown aspects of its pharmacokinetics especially related to the influence of covariates such as age, disease, or interactions linked to amantadine's renal elimination. As amantadine is used in Parkinson's disease and is considered a potential candidate in COVID treatment and other diseases, there is an unmet need for thorough understanding
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Leveraging QSP Models for MIPD: A Case Study for Warfarin/INR Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-24 Undine Falkenhagen, Larisa H. Cavallari, Julio D. Duarte, Charlotte Kloft, Stephan Schmidt, Wilhelm Huisinga
Warfarin dosing remains challenging due to substantial inter‐individual variability, which can lead to unsafe or ineffective therapy with standard dosing. Model‐informed precision dosing (MIPD) can help individualize warfarin dosing, requiring the selection of a suitable model. For models developed from clinical data, the dependence on the study design and population raises questions about generalizability
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From the Randomized AMBORA Trial to Clinical Practice: Comparison of Medication Errors in Oral Antitumor Therapy Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-24 Lisa Cuba, Pauline Dürr, Frank Dörje, Martin F. Fromm, Katja Schlichtig
The randomized AMBORA trial showed that medication errors are frequent in patients treated with oral antitumor therapeutics and that they can be substantially reduced by an intensified clinical pharmacological/pharmaceutical care program. While randomized controlled trials are essential to generate clinical evidence, their generalizability in real‐world is not always given. The AMBORA care program
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Hepatic Dysfunction Quantified by HepQuant DuO Outperforms Child‐Pugh Classification in Predicting the Pharmacokinetics of Ampreloxetine Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-24 Jitendra Kanodia, Hugh Giovinazzo, Wayne Yates, David L. Bourdet, Michael P. McRae, Steve M. Helmke, Gregory T. Everson
HepQuant tests quantify liver function from clearance of deuterium‐ and 13C‐labeled cholates administered either intravenously and orally (SHUNT) or orally (DuO). Hepatic impairment studies have relied on clinical or laboratory criteria like Child‐Pugh classification to categorize the degree of hepatic dysfunction. We compared HepQuant tests with Child‐Pugh classification in predicting the pharmacokinetics
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Unlocking the Capabilities of Large Language Models for Accelerating Drug Development Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-23 Wes Anderson, Ian Braun, Roopal Bhatnagar, Klaus Romero, Ramona Walls, Marco Schito, Jagdeep T. Podichetty
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Phenotype–Genotype Correlation Applying a Cocktail Approach and an Exome Chip Analysis Reveals Further Variants Contributing to Variation of Drug Metabolism Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-19 Ruwen Böhm, Henrike Bruckmueller, Stefan Oswald, Matthias Hübenthal, Meike Kaehler, Lena Ehmke, Jan Höcker, Werner Siegmund, Andre Franke, Ingolf Cascorbi
Although great progress has been made in the fine‐tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of pharmacogenetically relevant enzymes. The aim of this study was to analyze the additional contribution of sex and variants identified by exome chip analysis to the metabolic ratio of five probe drugs. A cocktail study applying dextromethorphan
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Safety of Monoclonal Antibodies Inhibiting PCSK9 in Pregnancy: Disproportionality Analysis in VigiBase® Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-19 Roberta Noseda, Francesca Bedussi, Alice Panchaud, Alessandro Ceschi
Safety data on the use of monoclonal antibodies inhibiting proprotein convertase subtilisin/kexin type 9 in pregnancy are scarce. This study queried VigiBase®, the World Health Organization global pharmacovigilance database, to search for signals of disproportionate reporting for pregnancy outcomes with alirocumab and evolocumab. As of November 22, 2023, there were 45 safety reports of exposure to
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Comparative Safety of Long‐Acting vs. Short‐Acting Erythropoiesis‐Stimulating Agents Among Patients Undergoing Hemodialysis Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-17 Raj Desai, Ikenna Unigwe, Munaza Riaz, Steven M. Smith, Ashutosh M. Shukla, Rajesh Mohandas, Nakyung Jeon, Haesuk Park
Both short‐acting (epoetin alfa or beta) and long‐acting (darbepoetin alfa or PEG‐epoetin) erythropoiesis‐stimulating agents (ESAs) are commonly prescribed for patients with kidney failure undergoing maintenance hemodialysis. We compared the risks of major adverse cardiovascular events (MACE) and of all‐cause mortality associated with receipt of short‐ vs. long‐acting ESAs. This retrospective cohort
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Model‐Informed Assessment of Probability of Phase 3 Success for Ritlecitinib in Patients with Moderate‐to‐Severe Ulcerative Colitis Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-17 Jessica Wojciechowski, Arnab Mukherjee, Christopher Banfield, Timothy Nicholas
Ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor, was evaluated in patients with ulcerative colitis (UC) in a phase 2b trial. Model‐informed drug development strategies were applied to bridge observations from phase 2b to predictions for a proposed phase 3 study design to assess the probability of achieving the target efficacy outcome. A longitudinal
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Best Practices for Pharmacokinetic Studies of New Chemical Entities Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-17 Ya‐Feng Wen, Piet H. van der Graaf
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Patient‐Centric Clinical Pharmacology: A Journey from Discovery to Recovery Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-17 Mohamed H. Shahin, Matthew L. Rizk
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Optimizing Dosage in Pharmacotherapy—Missing the Forest for the Trees Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-15 Susan M. Abdel‐Rahman, Andrew J. Farrell, N. Seth Berry, Gilbert J. Burckart
CONFLICT OF INTEREST The authors declared no competing interests for this work.
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Therapeutic Drug Monitoring of Oral Oncology Drugs: Another Example of Maslow's Hammer Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-12 Mark J. Ratain
While therapeutic drug monitoring is a potentially attractive strategy that can be utilized by clinical pharmacologists to optimize drug dosing, the costs and risks must be balanced against the potential benefits. However, there is great uncertainty regarding the optimal population dose for most oncology drugs, given the lack of randomized dose-ranging phase II trials. Therefore, efforts to individualize
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Identifying Drug–Drug Interactions in Spontaneous Reports Utilizing Signal Detection and Biological Plausibility Aspects Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-09 Elpida Kontsioti, Simon Maskell, Isobel Anderson, Munir Pirmohamed
Translational approaches can benefit post‐marketing drug safety surveillance through the growing availability of systems pharmacology data. Here, we propose a novel Bayesian framework for identifying drug–drug interaction (DDI) signals and differentiating between individual drug and drug combination signals. This framework is coupled with a systems pharmacology approach for automated biological plausibility
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The Use of Real‐World Evidence for Regulatory Decisions in China Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-03 Jiayue Xu, Wenkai Wu, Xia Zhang, Yan Ren, Minghong Yao, Mei Liu, Kang Zou, Wen Wang, Xin Sun
There is a growing demand for the use of high‐quality real‐world evidence (RWE) to support regulatory decision‐making worldwide and in China, which highlights the need for conducting literature reviews to evaluate the available data and evidence. This study aims to review the use of RWE in Chinese regulatory decisions and to summarize relevant regulatory and methodological considerations to inform
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Tracing Digital Therapeutics Research Across Medical Specialties: Evidence from ClinicalTrails.gov Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-04-02 Lars Masanneck, Ariel D. Stern
Digital therapeutics (DTx), evidence‐based software interventions for preventing, managing, or treating medical disorders, have rapidly evolved with healthcare's shift toward online, patient‐centric solutions. This study scrutinizes DTx clinical trials from 2005 to 2022, analyzing their growth, funding, underlying medical specialties, and other R&D characteristics, using ClinicalTrials.gov data. Our
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Oral SSTR5 Antagonist SCO‐240 for Growth Hormone Stimulation: A Phase I Single‐Dose Study in Healthy Individuals Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-29 Harunobu Nishizaki, Tomoya Kagawa, Jun Sugama, Akihiro Kobayashi, Yusuke Moritoh, Masanori Watanabe
Somatostatin inhibits endocrine and exocrine secretion in various tissues by acting on five somatostatin receptor subtypes (SSTR1–5). The clinical effects of SSTR5 antagonism remain unknown. Herein, we evaluated the effects of SCO‐240, an oral SSTR5 antagonist, in healthy individuals. This randomized, single‐center, double‐blind, placebo‐controlled, phase I study included healthy Japanese and White
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Impact of COVID‐19 on the Conduct and Design of Clinical Trials: IQ Consortium Perspective Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-27 Mohamed‐Eslam F. Mohamed, Sandhya Girish, Rita Humeniuk, Silpa Nuthalapati, Amit Desai, Amita Datta‐Mannan, Ferdous Gheyas, Jitendra Kanodia, Sravanthi Cheeti, Tong Zhu
To assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on clinical trials design and conduct, a Working Group was formed by the Clinical Pharmacology Leadership Group within the International Consortium for Innovation and Quality in Pharmaceutical Development. The Working Group collected and summarized data for IQ member companies' experience on impact of the pandemic on design and
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Transdermal Nicotine Patch Increases the Number and Function of Endothelial Progenitor Cells in Young Healthy Nonsmokers without Adverse Hemodynamic Effects Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-26 Yen‐Yu Liu, Ting‐Yi Tien, Chung‐Lieh Hung, Yih‐Jer Wu, Cheng‐Huang Su, Hung‐I Yeh
Transdermal nicotine patches (TNPs), administering nicotine into the bloodstream through skin, have been widely used as nicotine replacement therapy, and exposure to nicotine can be detected by measurement of plasma cotinine concentration. In animal studies, nicotine treatment could increase the number of endothelial progenitor cells (EPCs), but the effect of TNPs on circulating EPCs and their activity
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Regulatory Issues of Platform Trials: Learnings from EU-PEARL Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-26 Quynh Lan Nguyen, Katharina Hees, Sabina Hernandez Penna, Franz König, Martin Posch, Marta Bofill Roig, Elias Laurin Meyer, Michaela Maria Freitag, Tom Parke, Maximilian Otte, Hans-Peter Dauben, Tobias Mielke, Cecile Spiertz, Peter Mesenbrink, Madhavi Gidh-Jain, Suzanne Pierre, Salvatore Morello, Benjamin Hofner
Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and
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Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long-Acting Intramuscular Injection in Real-World People with HIV Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-22 Paul Thoueille, Susana Alves Saldanha, Fabian Schaller, Eva Choong, François Veuve, Aline Munting, Matthias Cavassini, Dominique Braun, Huldrych F. Günthard, Jessy J. Duran Ramirez, Bernard Surial, Hansjakob Furrer, Andri Rauch, Pilar Ustero, Alexandra Calmy, Marcel Stöckle, Caroline Di Benedetto, Enos Bernasconi, Patrick Schmid, Catia Marzolini, François R. Girardin, Thierry Buclin, Laurent A. Decosterd
Long-acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir
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Considerations for Industry—Preparing for the FDA Model‐Informed Drug Development (MIDD) Paired Meeting Program Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-23 Gerald R. Galluppi, Malidi Ahamadi, Souvik Bhattacharya, Nageshwar Budha, Ferdous Gheyas, Chi‐Chung Li, Yuan Chen, Anne‐Gaëlle Dosne, Niels Rode Kristensen, Mindy Magee, Mahesh N. Samtani, Vikram Sinha, Kunal Taskar, Vijay V. Upreti, Jianning Yang, Jack Cook
A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision‐making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD
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A Benefit–Risk Conceptual Framework for Biologic Use During Pregnancy: A Mini‐Review Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-20 Laura M. Bozzi, Melanie H. Jacobson, Emily Yost, Anna Sheahan, Joseph Cafone, Yosuke Komatsu, Lisa Schwartz, Bennett Levitan, Robert M. Nelson
Recent reports related to in utero exposure of marketed immunosuppressive biologics led to clinical recommendations to delay live vaccinations for infants due to the concern of reduced vaccine effectiveness and/or increased risk of vaccine‐related disease. These delays can increase the risk of children contracting vaccine preventable diseases, yet the alternative cessation of biologics during pregnancy
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Agreement about Availability of Alternative Treatments for Innovative Drugs Assessed by the EMA and HTA Organizations Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-20 Jorge Madrid Paredes, Jan‐Willem Versteeg, Rick A. Vreman, Lourens T. Bloem
The European Medicines Agency (EMA) and European national/regional health technology assessment (HTA) organizations consider the availability of existing treatments when evaluating a new drug. Since disagreement about the availability of alternative treatments may impact patient access to new drugs, this study aimed to investigate whether the EMA and HTA organizations agreed on the availability of
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Artificial Intelligence/Machine Learning: The New Frontier of Clinical Pharmacology and Precision Medicine Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-20 Qi Liu, Amita Joshi, Joseph F. Standing, Piet H. van der Graaf
In recent years, artificial intelligence (AI) and machine learning (ML) have emerged as transformative forces driving innovation across various sectors. This themed issue of Clinical Pharmacology & Therapeutics (CPT) is dedicated to AI/ML Innovations (Figure 1), showcasing a wide range of opportunities for applying these technologies in clinical pharmacology. AI/ML enable the application of novel methods
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A Genome‐Wide Association Study of Endoxifen Serum Concentrations and Adjuvant Tamoxifen Efficacy in Early‐Stage Breast Cancer Patients Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-19 Anabel Beatriz Sanchez‐Spitman, Stefan Böhringer, Vincent Olaf Dezentjé, Hans Gelderblom, Jesse Joachim Swen, Henk‐Jan Guchelaar
Tamoxifen is part of the standard of care of endocrine therapy for adjuvant treatment of breast cancer. However, survival outcomes with tamoxifen are highly variable. The concentration of endoxifen, the 30–100 times more potent metabolite of tamoxifen and bioactivated by the CYP2D6 enzyme, has been described as the most relevant metabolite of tamoxifen metabolism. A genome‐wide association study (GWAS)
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Clinical Pharmacology Considerations for the “Off‐the‐Shelf” Allogeneic Cell Therapies Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-19 Hardik Mody, Dhruvitkumar S. Sutaria, Dale Miles
Autologous chimeric antigen receptor T‐cell (CAR‐T) therapies have garnered unprecedented clinical success with multiple regulatory approvals for the treatment of various hematological malignancies. However, there are still several clinical challenges that limit their broad utilization for aggressive disease conditions. To address some of these challenges, allogeneic cell therapies are evaluated as
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Predicting the Long‐Term Effects of Therapeutic Neutralization of Oncostatin M on Human Hematopoiesis Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-19 Anders Thorsted, Chiara Zecchin, Alienor Berges, Mats O. Karlsson, Lena E. Friberg
Therapeutic neutralization of Oncostatin M (OSM) causes mechanism‐driven anemia and thrombocytopenia, which narrows the therapeutic window complicating the selection of doses (and dosing intervals) that optimize efficacy and safety. We utilized clinical data from studies of an anti‐OSM monoclonal antibody (GSK2330811) in healthy volunteers (n = 49) and systemic sclerosis patients (n = 35), to quantitatively
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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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A Case to Support the Continued Use of Rifampin in Clinical Drug–Drug Interaction Studies Clin. Pharmacol. Ther. (IF 6.7) Pub Date : 2024-03-18 Joel P. Bercu, David J. Ponting, Sharon L. Ripp, Krista L. Dobo, Rheem A. Totah, Jayaprakasam Bolleddula
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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