Association of Pharmacogenomic Phenotypes in CYP2D6, CYP2C9, CYP2C19, and CYP3A5 on Polypharmacy in Veterans
This study evaluates the effect that pharmacogenes may have on prevalence of polypharmacy. This retrospective cohort study included patients with VA prescriptions who underwent PGx testing. We quantified prescriptions active or recently expired at the time of PGx testing. We constructed two co-primary polypharmacy (≥10 medications) end points: (i) based on all medications and (ii) requiring that at least one medication was affected by a pharmacogene of interest. Pharmacogenes and actionable phenotypes of interest included poor and ultrarapid metabolizers for CYP2D6, CYP2C9, and CYP2C19 and intermediate and normal metabol...
Source: Clinical Pharmacology and Therapeutics - May 22, 2024 Category: Drugs & Pharmacology Authors: Linas Krulikas Jill Bates Catherine Chanfreau Heather Coleman Shawn Dalton Deepak Voora Source Type: research

Association of Pharmacogenomic Phenotypes in CYP2D6, CYP2C9, CYP2C19, and CYP3A5 on Polypharmacy in Veterans
This study evaluates the effect that pharmacogenes may have on prevalence of polypharmacy. This retrospective cohort study included patients with VA prescriptions who underwent PGx testing. We quantified prescriptions active or recently expired at the time of PGx testing. We constructed two co-primary polypharmacy (≥10 medications) end points: (i) based on all medications and (ii) requiring that at least one medication was affected by a pharmacogene of interest. Pharmacogenes and actionable phenotypes of interest included poor and ultrarapid metabolizers for CYP2D6, CYP2C9, and CYP2C19 and intermediate and normal metabol...
Source: Clinical Pharmacology and Therapeutics - May 22, 2024 Category: Drugs & Pharmacology Authors: Linas Krulikas Jill Bates Catherine Chanfreau Heather Coleman Shawn Dalton Deepak Voora Source Type: research

Association of Pharmacogenomic Phenotypes in CYP2D6, CYP2C9, CYP2C19, and CYP3A5 on Polypharmacy in Veterans
This study evaluates the effect that pharmacogenes may have on prevalence of polypharmacy. This retrospective cohort study included patients with VA prescriptions who underwent PGx testing. We quantified prescriptions active or recently expired at the time of PGx testing. We constructed two co-primary polypharmacy (≥10 medications) end points: (i) based on all medications and (ii) requiring that at least one medication was affected by a pharmacogene of interest. Pharmacogenes and actionable phenotypes of interest included poor and ultrarapid metabolizers for CYP2D6, CYP2C9, and CYP2C19 and intermediate and normal metabol...
Source: Clinical Pharmacology and Therapeutics - May 22, 2024 Category: Drugs & Pharmacology Authors: Linas Krulikas Jill Bates Catherine Chanfreau Heather Coleman Shawn Dalton Deepak Voora Source Type: research

Optimizing Early Clinical Investigations in Cancer Immunotherapy: The Translational Journey of RG6292, a Novel, Selective Treg-Depleting Antibody
Clin Pharmacol Ther. 2024 May 20. doi: 10.1002/cpt.3303. Online ahead of print.ABSTRACTThe multifaceted IL-2/IL-2R biology and its modulation by promising therapeutic agents are highly relevant topics in the cancer immunotherapy field. A novel CD25-Treg-depleting antibody (Vopikitug, RG6292) has been engineered to preserve IL-2 signaling on effector T cells to enhance effector activation and antitumor immunity, and is currently being evaluated in the clinic. The Entry into Human-enabling framework described here investigated the characteristics of RG6292, from in vitro quantification of CD25 and RG6292 pharmacology using h...
Source: Clinical Pharmacology and Therapeutics - May 21, 2024 Category: Drugs & Pharmacology Authors: Sara Belli Maria Amann Lucy Hutchinson Laur ène Pousse Afsaneh Abdolzade-Bavil Nicole Justies Bjoern Jacobsen Corinne Ploix Eleni Tselempi Vinko Tosevski Hans Koll Gabriel Schnetzler Christophe Boetsch Estelle Marrer-Berger Source Type: research

Oral Drug Dosing After Gastric Bypass and Diet-Induced Weight Loss: Simpler Than We Think? Lessons Learned From the COCKTAIL Study
This article summarizes the lessons learned from the COCKTAIL study: an open, three-armed, single-center study including patients with obesity scheduled for treatment with Roux-en-Y gastric bypass (RYGB) or nonsurgical calorie restriction, and a normal- to overweight control group. The clinical implications of the results from multiple peer-reviewed articles describing the effects of RYGB, severe caloric restriction, weight loss, and type 2 diabetes on the in vivo activity and protein expression of drug-metabolizing enzymes (cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 3A) and transporters (DMETs; organic anion-transporting p...
Source: Clinical Pharmacology and Therapeutics - May 21, 2024 Category: Drugs & Pharmacology Authors: Kine Eide Kvitne J øran Hjelmesæth Markus Hovd Rune Sandbu Line Kristin Johnson Shalini Andersson Cecilia Karlsson Hege Christensen Rasmus Jansson-L öfmark Anders Åsberg Ida Robertsen Source Type: research

Trust in the Food and Drug Administration: A  National Survey Study
Clin Pharmacol Ther. 2024 May 16. doi: 10.1002/cpt.3292. Online ahead of print.ABSTRACTBuilding trust in public health agencies like the US Food and Drug Administration (FDA) has become a key government priority. Understanding the roots of FDA mistrust is important if the agency is to develop targeted messaging and reforms aimed at building confidence in the agency. We conducted a survey of 2,021 respondents in the US probing attitudes toward the FDA. The primary outcome was FDA trust, defined as the mean score that each respondent assigned to the FDA across four prespecified axes: (1) competence and effectiveness; (2) com...
Source: Clinical Pharmacology and Therapeutics - May 17, 2024 Category: Drugs & Pharmacology Authors: William B Feldman Leah Z Rand Daniel Carpenter Massimiliano Russo Anushka Bhaskar Zhigang Lu Eric G Campbell Jonathan Darrow Aaron S Kesselheim Source Type: research

Trust in the Food and Drug Administration: A  National Survey Study
Clin Pharmacol Ther. 2024 May 16. doi: 10.1002/cpt.3292. Online ahead of print.ABSTRACTBuilding trust in public health agencies like the US Food and Drug Administration (FDA) has become a key government priority. Understanding the roots of FDA mistrust is important if the agency is to develop targeted messaging and reforms aimed at building confidence in the agency. We conducted a survey of 2,021 respondents in the US probing attitudes toward the FDA. The primary outcome was FDA trust, defined as the mean score that each respondent assigned to the FDA across four prespecified axes: (1) competence and effectiveness; (2) com...
Source: Clinical Pharmacology and Therapeutics - May 17, 2024 Category: Drugs & Pharmacology Authors: William B Feldman Leah Z Rand Daniel Carpenter Massimiliano Russo Anushka Bhaskar Zhigang Lu Eric G Campbell Jonathan Darrow Aaron S Kesselheim Source Type: research

Trust in the Food and Drug Administration: A  National Survey Study
Clin Pharmacol Ther. 2024 May 16. doi: 10.1002/cpt.3292. Online ahead of print.ABSTRACTBuilding trust in public health agencies like the US Food and Drug Administration (FDA) has become a key government priority. Understanding the roots of FDA mistrust is important if the agency is to develop targeted messaging and reforms aimed at building confidence in the agency. We conducted a survey of 2,021 respondents in the US probing attitudes toward the FDA. The primary outcome was FDA trust, defined as the mean score that each respondent assigned to the FDA across four prespecified axes: (1) competence and effectiveness; (2) com...
Source: Clinical Pharmacology and Therapeutics - May 17, 2024 Category: Drugs & Pharmacology Authors: William B Feldman Leah Z Rand Daniel Carpenter Massimiliano Russo Anushka Bhaskar Zhigang Lu Eric G Campbell Jonathan Darrow Aaron S Kesselheim Source Type: research

Trust in the Food and Drug Administration: A  National Survey Study
Clin Pharmacol Ther. 2024 May 16. doi: 10.1002/cpt.3292. Online ahead of print.ABSTRACTBuilding trust in public health agencies like the US Food and Drug Administration (FDA) has become a key government priority. Understanding the roots of FDA mistrust is important if the agency is to develop targeted messaging and reforms aimed at building confidence in the agency. We conducted a survey of 2,021 respondents in the US probing attitudes toward the FDA. The primary outcome was FDA trust, defined as the mean score that each respondent assigned to the FDA across four prespecified axes: (1) competence and effectiveness; (2) com...
Source: Clinical Pharmacology and Therapeutics - May 17, 2024 Category: Drugs & Pharmacology Authors: William B Feldman Leah Z Rand Daniel Carpenter Massimiliano Russo Anushka Bhaskar Zhigang Lu Eric G Campbell Jonathan Darrow Aaron S Kesselheim Source Type: research

Optimizing Clinical Translation of Bispecific T-cell Engagers through Context Unification with a Quantitative Systems Pharmacology Model
In this study, we developed a Quantitative Systems Pharmacology (QSP) model, through context unification, that can facilitate the translation of bsTCEs preclinical data into clinical activity. Through characterizing the formation dynamics of immunological synapse (IS) induced by bsTCEs, this model unifies a broad range of contexts related to target affinity, tumor characteristics, and immunological conditions. After rigorous calibration using both experimental and clinical data, the model enables consistent translation of drug potency observed under diverse experimental conditions into predictable exposure-response relatio...
Source: Clinical Pharmacology and Therapeutics - May 16, 2024 Category: Drugs & Pharmacology Authors: Xiaozhi Liao Timothy Qi Jiawei Zhou Can Liu Yanguang Cao Source Type: research

Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper
Clin Pharmacol Ther. 2024 May 16. doi: 10.1002/cpt.3298. Online ahead of print.ABSTRACTThe landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current pract...
Source: Clinical Pharmacology and Therapeutics - May 16, 2024 Category: Drugs & Pharmacology Authors: Divya Samineni Karthik Venkatakrishnan Ahmed A Othman Yazdi K Pithavala Srinivasu Poondru Chirag Patel Pavan Vaddady Wendy Ankrom Saroja Ramanujan Nageshwar Budha Michael Wu Nahor Haddish-Berhane Holger Fritsch Azher Hussain Jitendra Kanodia Meng Li Mengy Source Type: research

Optimizing Clinical Translation of Bispecific T-cell Engagers through Context Unification with a Quantitative Systems Pharmacology Model
In this study, we developed a Quantitative Systems Pharmacology (QSP) model, through context unification, that can facilitate the translation of bsTCEs preclinical data into clinical activity. Through characterizing the formation dynamics of immunological synapse (IS) induced by bsTCEs, this model unifies a broad range of contexts related to target affinity, tumor characteristics, and immunological conditions. After rigorous calibration using both experimental and clinical data, the model enables consistent translation of drug potency observed under diverse experimental conditions into predictable exposure-response relatio...
Source: Clinical Pharmacology and Therapeutics - May 16, 2024 Category: Drugs & Pharmacology Authors: Xiaozhi Liao Timothy Qi Jiawei Zhou Can Liu Yanguang Cao Source Type: research

Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper
Clin Pharmacol Ther. 2024 May 16. doi: 10.1002/cpt.3298. Online ahead of print.ABSTRACTThe landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current pract...
Source: Clinical Pharmacology and Therapeutics - May 16, 2024 Category: Drugs & Pharmacology Authors: Divya Samineni Karthik Venkatakrishnan Ahmed A Othman Yazdi K Pithavala Srinivasu Poondru Chirag Patel Pavan Vaddady Wendy Ankrom Saroja Ramanujan Nageshwar Budha Michael Wu Nahor Haddish-Berhane Holger Fritsch Azher Hussain Jitendra Kanodia Meng Li Mengy Source Type: research

Biomarkers for Precision Patient Selection in Cancer Therapy Approvals in the US, from 2011 to 2023
Clin Pharmacol Ther. 2024 May 15. doi: 10.1002/cpt.3306. Online ahead of print.ABSTRACTDuring the period of 2011-2023, the US Food and Drug Administration (US FDA) granted 139 accelerated and 329 regular approvals for 86 and 152 cancer therapeutic products, respectively. The percentage of approvals for a biomarker-defined population was numerically higher in accelerated approvals in comparison to regular approvals, that is, 48% vs. 40%. From 2011-2016 to 2017-2023, there was an increasing number of approvals with biomarker-defined populations in lung and breast cancers, serving as the primary driver for the overall increas...
Source: Clinical Pharmacology and Therapeutics - May 15, 2024 Category: Drugs & Pharmacology Authors: Yannan Nancy Dou Christian Grimstein Jacques Mascaro Jian Wang Source Type: research

Moving the Needle for Oncology Dose Optimization: A Call for Action
Clin Pharmacol Ther. 2024 Jun;115(6):1187-1197. doi: 10.1002/cpt.3263.NO ABSTRACTPMID:38736240 | DOI:10.1002/cpt.3263 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - May 13, 2024 Category: Drugs & Pharmacology Authors: Karthik Venkatakrishnan Priya Jayachandran Shirley K Seo Piet H van der Graaf John A Wagner Neeraj Gupta Source Type: research