A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors

EJNMMI Research

Yuh-Min Chen¹  Wen-Sheng Huang²  Shyh-Jen Wang²  Chi-Mu Chuang³  Peter Mu-Hsin Chang⁴  Ta-Chung Chao⁴  Ming-Huang Chen⁴  Yee Chao⁴  Hao-Wei Teng⁴  Keng-Li Lan⁵  Tzu-Ping Lin⁶  Gann Ting⁷  Su-Jung Chen⁷  Chih-Hsien Chang⁷  Te-Wei Lee⁷  Ya-Jen Chang⁷  Yuan-Ruei Huang⁷ 

[1] 0000 0004 0604 5314, grid.278247.c, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;0000 0004 0604 5314, grid.278247.c, Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;0000 0004 0604 5314, grid.278247.c, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan;0000 0001 0425 5914, grid.260770.4, School of Medicine, National Yang-Ming University, Taipei, Taiwan;0000 0004 0604 5314, grid.278247.c, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd, Pei-Tou District, Taipei City, Taiwan;0000 0004 0604 5314, grid.278247.c, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd, Pei-Tou District, Taipei City, Taiwan;0000 0001 0425 5914, grid.260770.4, Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan;0000 0004 0604 5314, grid.278247.c, Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan;0000 0004 0638 7461, grid.482644.8, Institute of Nuclear Energy Research, Taoyuan, Taiwan;

关键词: Re;    Liposome;    Biodistribution;    Dosimetry;    phase 0 exploratory IND;   

DOI  :  10.1186/s13550-019-0509-6

来源: publisher

【 摘 要 】

BackgroundLiposomes are drug nano-carriers that are capable of targeting therapeutics to tumor sites because of enhanced permeability retention (EPR). In several preclinical studies with various tumor-bearing mice models, 188Re-liposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use.This study conducts a phase 0 low-radioactivity clinical trial of nano-targeted radiotherapeutics 188Re-liposome to evaluate the effectiveness with which it targets tumors and the pharmacokinetics, biodistribution, dosimetry, and its safety in use. Twelve patients with metastatic cancers are studied in this trial. Serial whole-body scans and SPECT/CT are taken at 1, 4, 8, 24, 48, and 72 h after intravenous injection of 111 MBq of 188Re-liposome. The effectiveness with which tumors are targeted, the pharmacokinetics, biodistribution, dosimetry, and safety are evaluated using the VelocityAI and OLINDA/EXM software. Blood samples are collected at different time points for a pharmacokinetics study and a safety evaluation that involves monitoring changes in liver, renal, and hematological functions.ResultsThe T½z for 188Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h, respectively. The doses of radiation that are absorbed to vital organs such as the liver, spleen, lung, kidney, and bone marrow are 0.92 ± 0.35, 1.38 ± 1.81, 0.58 ± 0.28, 0.32 ± 0.09, and 0.06 ± 0.01 mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of 188Re-liposome. 188Re-liposome is absorbed by metastatic tumor lesions and the normal reticuloendothelial (RES) system. Certain patients exhibit a therapeutic response.ConclusionThis phase 0 exploratory IND study shows that nanocarrier 188Re-liposome achieves favorable tumor accumulation and tumor to normal organ uptake ratios for a subset of cancer patients. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial.Trial registrationTaiwan FDA MA1101G0 (Jan 31, 2012).

【 授权许可】

CC BY