Article
Pharmacology & Pharmacy
Blaise Pasquiers, Salih Benamara, Mathieu Felices, David Ternant, Xavier Decleves, Alicja Puszkiel
Summary: The objective of this study was to develop a generic physiologically based pharmacokinetic (PBPK) translational approach for monoclonal antibodies (mAb) using open-source software. The translation of bevacizumab was used as a case example to demonstrate the model. The predictions of the model were within an acceptable range for both area under the concentration-time curve (AUC) and maximum concentration (C-max).
Review
Biochemistry & Molecular Biology
Blaise Pasquiers, Salih Benamara, Mathieu Felices, Laurent Nguyen, Xavier Decleves
Summary: This article discusses the growing interest in therapeutic monoclonal antibodies (mAbs) for various diseases, focusing on their complex pharmacokinetic profiles. It reviews the existing PK modeling approaches to translate mAbs PK from animal models to humans, ranging from empirical models to PBPK models. The emphasis is on population PK methods, linear PK aspects, and TMDD mechanisms of mAbs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Shihao Hu, Amita Datta-Mannan, David Z. D'Argenio
Summary: An integrated physiologically based modeling framework is proposed to predict pharmacokinetics and bioavailability of subcutaneously administered monoclonal antibodies in cynomolgus monkeys. The model incorporates in silico structure-derived metrics to characterize the antibody size, charge, and hydrophobicity, and successfully predicts the pharmacokinetics of different mAbs following intravenous and subcutaneous administration.
Article
Pharmacology & Pharmacy
Zinnia P. Parra-Guillen, Aymara Sancho-Araiz, Kapil Mayawala, Sara Zalba, Maria J. Garrido, Dinesh de Alwis, Inaki F. Troconiz, Tomoko Freshwater
Summary: This study developed a mechanistic modeling framework to quantitatively characterize the kinetics and distribution of V937 oncolytic virus in cancer patients. The model accurately described the changes in V937 mRNA levels and tumor size and revealed the importance of viral distribution and infectivity in clinical therapy.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Pharmacology & Pharmacy
Tommy R. Li, Manash Chatterjee, Mallika Lala, Anson K. Abraham, Tomoko Freshwater, Lokesh Jain, Vikram Sinha, Dinesh P. de Alwis, Kapil Mayawala
Summary: This article outlines a pragmatic dose selection strategy for immuno-oncology and other targeted monoclonal antibodies, using pembrolizumab as an example. Through simulations and randomized dose comparison studies, the recommended phase II dose (RP2D) of 200 mg every 3 weeks was confirmed as the pivotal dose for achieving optimal target engagement.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Multidisciplinary Sciences
Dimitris G. Patsatzis, Shengjia Wu, Dhaval K. Shah, Dimitris A. Goussis
Summary: This article demonstrates how algorithmic asymptotic analysis can provide system level understanding and predictions on the response of multi-scale pharmacokinetics systems. The algorithm identifies the constraints generated by the fast part of the model and the components of the slow part that drive the system within these constraints. The findings produced by the algorithm are shown to be more accurate and provide additional insights compared to traditional methodologies.
SCIENTIFIC REPORTS
(2022)
Article
Pharmacology & Pharmacy
Peter Bloomingdale, Daniela Bumbaca-Yadav, Jonathan Sugam, Steve Grauer, Brad Smith, Svetlana Antonenko, Michael Judo, Glareh Azadi, Ka Lai Yee
Summary: The objective of this study was to develop a mechanistic mathematical model to enhance our understanding of tau antibody pharmacokinetics and pharmacodynamics in animals and humans, supporting the preclinical development and clinical translation of therapeutic antibodies for the treatment of Alzheimer's disease.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Cell Biology
Zhehua Shao, Yangxia Tan, Qingya Shen, Li Hou, Bingpeng Yao, Jiao Qin, Peiyu Xu, Chunyou Mao, Li-Nan Chen, Huibing Zhang, Dan-Dan Shen, Chao Zhang, Weijie Li, Xufei Du, Fei Li, Zhi-Hua Chen, Yi Jiang, H. Eric Xu, Songmin Ying, Honglei Ma, Yan Zhang, Huahao Shen
Summary: This study presents cryo-electron microscopy structures of two human CC chemokine receptor-G-protein complexes, providing insights into the mechanisms of signal transduction and receptor activation. The findings offer important structural information and a research foundation for drug design targeting chemokine receptors.
Article
Medicine, General & Internal
Rachel A. Bender Ignacio, Kara W. Chew, Carlee Moser, Judith S. Currier, Joseph J. Eron, Arzhang Cyrus Javan, Mark J. Giganti, Evgenia Aga, Michael Gibbs, Herve Tchouakam Kouekam, Eva Johnsson, Mark T. Esser, Keila Hoover, Gene Neytman, Matthew Newell, Eric S. Daar, William Fischer, Courtney V. Fletcher, Jonathan Z. Li, Alexander L. Greninger, Robert W. Coombs, Michael D. Hughes, Davey Smith, David Alain Wohl
Summary: These two clinical trials showed that tixagevimab and cilgavimab monoclonal antibodies were safe and effective for treating early COVID-19, but did not change the time to symptom improvement. The treatment outcomes were better for the intramuscular injection.
Article
Oncology
Stephanie Durand-Panteix, Jacques Monteil, Magali Sage, Armand Garot, Marie Clavel, Amal Saidi, Julien Torgue, Michel Cogne, Isabelle Quelven
Summary: This study investigated the potential of alpha-RIT in combination with Pb-212-rituximab for NHL treatment using mouse lymphoma cells. Results showed significant tumor regression and increased survival using 277.5 kBq Pb-212-rituximab, highlighting the potency of alpha-RIT for NHL treatment.
BRITISH JOURNAL OF CANCER
(2021)
Article
Pharmacology & Pharmacy
Wenpeng Zhang, Yanan Xiang, Lingchao Wang, Furun Wang, Guanglu Li, Xiaomei Zhuang
Summary: The study aimed to construct a PBPK model to accelerate the translation of a humanized bispecific antibody against the Ebola virus. In-depth nonclinical pharmacokinetic studies were conducted in multiple animal models, and a mechanistic whole-body PBPK model was developed to predict the pharmacokinetic behaviors of the antibody in humans.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2022)
Article
Oncology
Pallawi Torka, Othman S. Akhtar, Nishitha M. Reddy, Bora E. Baysal, Angela Kader, Adrienne Groman, Jenna Nichols, Cory Mavis, Joseph D. Tario, AnneMarie W. Block, Sheila N. J. Sait, Paola Ghione, Suchitra Sundaram, Eugene R. Przespolewski, Alice Mohr, Ian Lund, Jessica Kostrewa, Kenneth McWhite, Joseph DeMarco, Michael Johnson, Andrea Darrall, Rosh-Neke Thomas-Talley, Paul K. Wallace, Vishala Neppalli, Alan Hutson, Francisco J. Hernandez-Ilizaliturri
Summary: This study evaluates the safety and efficacy of combining ofatumumab with HyperCVAD/MA in newly diagnosed MCL. The results show that this combination therapy leads to high rates of MRD negativity and improved overall survival in patients with MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with better outcomes.
Article
Immunology
Basudev Paudyal, Adam McNee, Pramila Rijal, B. Veronica Carr, Alejandro Nunez, John McCauley, Rodney S. Daniels, Alain R. Townsend, John A. Hammond, Elma Tchilian
Summary: Prophylactic intravenous administration of specific monoclonal antibodies in pigs showed significant reduction in lung pathology and virus loads, but not consistent reduction in nasal shedding. The effect on lung pathology and virus load is consistent across different doses, suggesting that lower doses may be effective in reducing disease severity.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Pharmacology & Pharmacy
Dong Wook Kang, Kyung Min Kim, Ju Hee Kim, Hea-Young Cho
Summary: This study evaluated the pharmacokinetics and distribution of pyronaridine, artesunate, and dihydroartemisinin in the lung and trachea using a minimal physiologically-based pharmacokinetic model. The results showed that pyronaridine was extensively distributed to the lung and trachea, while artesunate and dihydroartemisinin had lower concentrations. These findings provide a scientific basis for understanding the dose-exposure-response relationship of pyronaridine and artesunate for COVID-19 drug repurposing.
Article
Multidisciplinary Sciences
Xiaojie Yu, Christian M. Orr, H. T. Claude Chan, Sonya James, Christine A. Penfold, Jinny Kim, Tatyana Inzhelevskaya, C. Ian Mockridge, Kerry L. Cox, Jonathan W. Essex, Ivo Tews, Martin J. Glennie, Mark S. Cragg
Summary: Low affinity of immunomodulatory antibodies leads to greater activity through increased clustering, resulting in higher immune cell activation, T cell expansion, and antitumor activity. This discovery reveals a new mechanism for enhancing receptor activation across diverse receptor families and sheds light on the mechanism of antibody-mediated receptor signaling. Affinity engineering offers a rational, efficient, and tunable solution for delivering antibody-mediated receptor activity for the treatment of human disease.