Prediction of Human Pharmacokinetics of E0703, a Novel Radioprotective Agent, Using Physiologically Based Pharmacokinetic Modeling and an Interspecies Extrapolation Approach. 2024

Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China.

E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPlus, Lancaster, CA, USA). Furthermore, tissue distribution and the human PK profiles of different administration dosages and forms were predicted. The 0.002 L/h of CL and 0.005 L of Vss in mice were calculated and optimized from observed PK data. The plasma exposure of E0703 was availably predicted by the CL using the simple allometry (SA) method. The plasma concentration-time profiles of other dosages (20 and 40 mg) and two oral administrations (30 mg) were well-fitted to the observed values. In addition, the PK profile of target organs for E0703 exhibited a higher peak concentration (Cmax) and AUC than plasma. The developed E0703-PBPK model, which is precisely applicable to multiple species, benefits from further clinical development to predict PK in humans.

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D010599 Pharmacokinetics Dynamic and kinetic mechanisms of exogenous chemical DRUG LIBERATION; ABSORPTION; BIOLOGICAL TRANSPORT; TISSUE DISTRIBUTION; BIOTRANSFORMATION; elimination; and DRUG TOXICITY as a function of dosage, and rate of METABOLISM. LADMER, ADME and ADMET are abbreviations for liberation, absorption, distribution, metabolism, elimination, and toxicology. ADME,ADME-Tox,ADMET,Absorption, Distribution, Metabolism, Elimination, and Toxicology,Absorption, Distribution, Metabolism, and Elimination,Drug Kinetics,Kinetics, Drug,LADMER,Liberation, Absorption, Distribution, Metabolism, Elimination, and Response
D011837 Radiation-Protective Agents Drugs used to protect against ionizing radiation. They are usually of interest for use in radiation therapy but have been considered for other purposes, e.g. military. Radiation Protectant,Radiation Protective Agent,Radiation-Protective Agent,Radiation-Protective Drug,Radioprotective Agent,Radioprotective Agents,Radioprotective Drug,Agents, Radiation-Protective,Radiation Protectants,Radiation Protective Agents,Radiation-Protective Drugs,Radiation-Protective Effect,Radiation-Protective Effects,Radioprotective Drugs,Agent, Radiation Protective,Agent, Radiation-Protective,Agent, Radioprotective,Agents, Radiation Protective,Agents, Radioprotective,Drug, Radiation-Protective,Drug, Radioprotective,Drugs, Radiation-Protective,Drugs, Radioprotective,Effect, Radiation-Protective,Effects, Radiation-Protective,Protectant, Radiation,Protectants, Radiation,Protective Agent, Radiation,Protective Agents, Radiation,Radiation Protective Drug,Radiation Protective Drugs,Radiation Protective Effect,Radiation Protective Effects
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014018 Tissue Distribution Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. Distribution, Tissue,Distributions, Tissue,Tissue Distributions
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

Related Publications

Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
January 2015, EXCLI journal,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
January 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
January 2015, EXCLI journal,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
August 2018, Journal of pharmacokinetics and pharmacodynamics,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
January 2024, Journal of pharmaceutical sciences,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
April 2020, Biopharmaceutics & drug disposition,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
April 2019, Pharmaceutics,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
November 2022, Pharmaceutics,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
June 2019, Journal of pharmaceutical sciences,
Yun-Xuan Ge, and Zhuo Zhang, and Jia-Yi Yan, and Zeng-Chun Ma, and Yu-Guang Wang, and Cheng-Rong Xiao, and Xiao-Mei Zhuang, and Yue Gao
January 2014, Frontiers in pharmacology,
Copied contents to your clipboard!