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The 112th American Association for Cancer Research (AACR) Annual Meeting in 2021 will be held on April 10-15 and May 17-21 in virtual form.
In this grand event, a study based on the Chinese population in China shined on the international stage.
This study was led by the team of Professor Lin Shen from Peking University Cancer Hospital, and explored the pharmacokinetic (PK) characteristics of repetinib and its active metabolites in patients with gastrointestinal stromal tumor (GIST) in China.
The study was included in the conference POSTER (LB126) 1, this is another great news after Repetinib was approved for listing in China! Research background GIST is the most common mesenchymal tumor in gastrointestinal tumors, with an annual incidence of 10-15 per million2,3.
More than 30,000 people in China are diagnosed with GIST4 each year, and about 96.
5% of them carry KIT or PDGFRA gene mutations5.
Repetinib is a switch-controlled tyrosine kinase inhibitor that can broadly inhibit KIT and PDGFRA kinase signaling through a dual mechanism of action6.
Based on the results of INVICTUS study7, Repetinib has been approved for the fourth-line standard treatment of advanced GIST in the United States, Canada, Australia, China and Hong Kong.
The INVICTUS study is a single-arm, multi-center phase II bridging trial conducted in China (ZL-2307-002), which aims to evaluate the PK characteristics of repetinib and its active metabolite DP-5439 in Chinese GIST patients.
And use non-compartmental analysis (NCA) and population pharmacokinetic modeling analysis (Pop-PK) to compare the differences in drug exposure between Chinese and global patient populations.
Study results The PK exposure of repetinib and DP-5439 in Chinese patients is similar to that of global patients.
A total of 15 Chinese patients were included in the NCA analysis, and population pharmacokinetic modeling included a total of 379 patients from 3 studies.The baseline characteristics between the Chinese and global patient populations are basically similar.
According to the analysis data of non-compartmental model, after single and continuous oral repetinib, repetinib and its metabolite DP-5439 were detected in plasma, and moderate to large PK variations were observed (see Table 1 ).
After 15 days of continuous treatment, accumulation of repetinib was observed.
Compared to repetinib, the exposure of the active metabolite DP-5439 is slightly higher.
Overall, the PK exposure of repetinib and DP-5439 in Chinese patients is similar to that of global patients.
Table 1.
Overview of single-dose and multi-dose PK parameters *The difference between the geometric mean of Chinese patients and the geometric mean of global patients [ie (Geometric mean of Chinese patients-Geometric mean of global patients)/Geometric mean of global patients, expressed in absolute values].
Cmax: maximum plasma concentration; CV: coefficient of variation; NR: not reported.
Population pharmacokinetic studies showed that there was no significant difference in the exposure of repetinib and DP-5439 between Asian and non-Asian populations (P>0.
05, see Figure 1), between Chinese and non-Chinese populations There was no significant difference (P>0.
05, see Figure 2) Figure 1.
The effect of race on steady-state exposure AUCss: area under the steady-state plasma concentration-time curve; Cmax,ss: steady-state maximum plasma concentration; Cmin,ss: stable Figure 2.
The effect of the test area on steady-state exposure.
The conclusion of the study is that there is no significant difference in the PK exposure of repetinib and its active metabolite DP-5439 between the Chinese and global patient populations.
Looking to the future AACR was established in 1907 by 11 doctors and scientists who are interested in cancer research, with the aim of "deepening cancer research and promoting related knowledge".
It is estimated that they did not expect that they would directly become the veterans of the benchmarking organization in the cancer field.
AACR is the world's earliest and largest scientific organization dedicated to comprehensive, innovative and high-level cancer research.
It is an authoritative organization that publishes information on the causes, diagnosis, treatment and prevention of cancer. AACR always regards research, education, communication and cooperation in the prevention and treatment of cancer as the mission of the association, and stands at the forefront of cancer prevention and treatment by promoting the growth and dissemination of new cancer knowledge.
If there is an internal roll in the cancer field, AACR has to be the king.
The AACR annual meeting focuses on breakthrough research that can promote changes in clinical practice.
It brings together the most cutting-edge research results in the field of oncology and is a weather vane for global oncology research.
The pharmacokinetic data of the Chinese population released by repetinib at the AACR meeting has added confidence to the clinical journey of repetinib in China.
I look forward to the release of more repetinib data in the Chinese population in the future, benefiting more Chinese GIST patients.
About the authorProfessor Li Jian, chief physician, doctoral supervisor, deputy administrative director, deputy director of the Department of Digestive Oncology, Peking University Cancer Hospital, deputy director of the drug clinical trial organization, deputy chairman of the CSCO Gastrointestinal Stromal Tumor Specialized Committee, member and secretary of the CSCO Clinical Research Specialized Committee Long CSCO Colorectal Cancer Committee Standing Committee, Chinese Medical Doctor Association Surgery Branch, Gastrointestinal Stromal Tumor Committee Deputy Chairman, Chinese Medical Doctor Association MDT Special Committee Standing Committee and Youth Committee Chairman, Chinese Medical Doctor Association Colorectal Cancer Special Committee Liver Metastasis Group Deputy Chairman of the Standing Committee of the Chinese Anti-Cancer Association Gastrointestinal Stromal Tumor Committee Member of the Standing Committee and Deputy Secretary-General of the Chinese Anti-Cancer Association Cancer Drug Clinical Research Committee Member of the Colorectal Cancer Committee of the Chinese Anti-Cancer Association and Deputy Chairman of the Youth Committee Editorial Board Member of Electronic Journal of Rectal Diseases, Editorial Board Member of "Tumor Clinical and Research" References 1.
Jian Li, Jun Zhang, Xingye Wu et al.
Population and Non-Compartmental Pharmacokinetic Analysis of Ripretinib and its Active Metabolite in Chinese Patients with Gastrointestinal Stromal Tumor.
AACR 2021, LB126.
2.
Lostes-Bardaji M Julia,García-Illescas David,Valverde Claudia et al.
Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward.
[J] .
Ther Adv Med Oncol, 2021, 13 : 1758835920986498; 3.
Miettinen M, Lasota J.
Gastroenterol Clin North Am 2013;42:399-415; 4.
Rosa, K.
OncLive.
Available at: step-toward-chinese-approval-for-advancedgist.
Accessed on 3 March 2021; 5.
Li Jian,Shen Lin,The current status of and prospects in research regarding gastrointestinal stromal tumors in China.
[J] .
Cancer, 2020, null: 2048-2053.
6.
Smith Bryan D,Kaufman Michael D ,Lu Wei-Ping et al.
Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.
[J] .
Cancer Cell, 2019, 35: 738-751.
e9.
7.
Blay Jean-Yves,Serrano César,Heinrich Michael C et al.
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.
[J] .
Lancet Oncol, 2020, 21: 923-934.
Kaufman Michael D,Lu Wei-Ping et al.
Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.
[J] .
Cancer Cell, 2019, 35: 738 -751.
e9.
7.
Blay Jean-Yves,Serrano César,Heinrich Michael C et al.
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.
[J ] .
Lancet Oncol, 2020, 21: 923-934.
Kaufman Michael D,Lu Wei-Ping et al.
Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.
[J] .
Cancer Cell, 2019, 35: 738 -751.
e9.
7.
Blay Jean-Yves,Serrano César,Heinrich Michael C et al.
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.
[J ] .
Lancet Oncol, 2020, 21: 923-934.
placebo-controlled, phase 3 trial.
[J] .
Lancet Oncol, 2020, 21: 923-934.
placebo-controlled, phase 3 trial.
[J] .
Lancet Oncol, 2020, 21: 923-934.
In this grand event, a study based on the Chinese population in China shined on the international stage.
This study was led by the team of Professor Lin Shen from Peking University Cancer Hospital, and explored the pharmacokinetic (PK) characteristics of repetinib and its active metabolites in patients with gastrointestinal stromal tumor (GIST) in China.
The study was included in the conference POSTER (LB126) 1, this is another great news after Repetinib was approved for listing in China! Research background GIST is the most common mesenchymal tumor in gastrointestinal tumors, with an annual incidence of 10-15 per million2,3.
More than 30,000 people in China are diagnosed with GIST4 each year, and about 96.
5% of them carry KIT or PDGFRA gene mutations5.
Repetinib is a switch-controlled tyrosine kinase inhibitor that can broadly inhibit KIT and PDGFRA kinase signaling through a dual mechanism of action6.
Based on the results of INVICTUS study7, Repetinib has been approved for the fourth-line standard treatment of advanced GIST in the United States, Canada, Australia, China and Hong Kong.
The INVICTUS study is a single-arm, multi-center phase II bridging trial conducted in China (ZL-2307-002), which aims to evaluate the PK characteristics of repetinib and its active metabolite DP-5439 in Chinese GIST patients.
And use non-compartmental analysis (NCA) and population pharmacokinetic modeling analysis (Pop-PK) to compare the differences in drug exposure between Chinese and global patient populations.
Study results The PK exposure of repetinib and DP-5439 in Chinese patients is similar to that of global patients.
A total of 15 Chinese patients were included in the NCA analysis, and population pharmacokinetic modeling included a total of 379 patients from 3 studies.The baseline characteristics between the Chinese and global patient populations are basically similar.
According to the analysis data of non-compartmental model, after single and continuous oral repetinib, repetinib and its metabolite DP-5439 were detected in plasma, and moderate to large PK variations were observed (see Table 1 ).
After 15 days of continuous treatment, accumulation of repetinib was observed.
Compared to repetinib, the exposure of the active metabolite DP-5439 is slightly higher.
Overall, the PK exposure of repetinib and DP-5439 in Chinese patients is similar to that of global patients.
Table 1.
Overview of single-dose and multi-dose PK parameters *The difference between the geometric mean of Chinese patients and the geometric mean of global patients [ie (Geometric mean of Chinese patients-Geometric mean of global patients)/Geometric mean of global patients, expressed in absolute values].
Cmax: maximum plasma concentration; CV: coefficient of variation; NR: not reported.
Population pharmacokinetic studies showed that there was no significant difference in the exposure of repetinib and DP-5439 between Asian and non-Asian populations (P>0.
05, see Figure 1), between Chinese and non-Chinese populations There was no significant difference (P>0.
05, see Figure 2) Figure 1.
The effect of race on steady-state exposure AUCss: area under the steady-state plasma concentration-time curve; Cmax,ss: steady-state maximum plasma concentration; Cmin,ss: stable Figure 2.
The effect of the test area on steady-state exposure.
The conclusion of the study is that there is no significant difference in the PK exposure of repetinib and its active metabolite DP-5439 between the Chinese and global patient populations.
Looking to the future AACR was established in 1907 by 11 doctors and scientists who are interested in cancer research, with the aim of "deepening cancer research and promoting related knowledge".
It is estimated that they did not expect that they would directly become the veterans of the benchmarking organization in the cancer field.
AACR is the world's earliest and largest scientific organization dedicated to comprehensive, innovative and high-level cancer research.
It is an authoritative organization that publishes information on the causes, diagnosis, treatment and prevention of cancer. AACR always regards research, education, communication and cooperation in the prevention and treatment of cancer as the mission of the association, and stands at the forefront of cancer prevention and treatment by promoting the growth and dissemination of new cancer knowledge.
If there is an internal roll in the cancer field, AACR has to be the king.
The AACR annual meeting focuses on breakthrough research that can promote changes in clinical practice.
It brings together the most cutting-edge research results in the field of oncology and is a weather vane for global oncology research.
The pharmacokinetic data of the Chinese population released by repetinib at the AACR meeting has added confidence to the clinical journey of repetinib in China.
I look forward to the release of more repetinib data in the Chinese population in the future, benefiting more Chinese GIST patients.
About the authorProfessor Li Jian, chief physician, doctoral supervisor, deputy administrative director, deputy director of the Department of Digestive Oncology, Peking University Cancer Hospital, deputy director of the drug clinical trial organization, deputy chairman of the CSCO Gastrointestinal Stromal Tumor Specialized Committee, member and secretary of the CSCO Clinical Research Specialized Committee Long CSCO Colorectal Cancer Committee Standing Committee, Chinese Medical Doctor Association Surgery Branch, Gastrointestinal Stromal Tumor Committee Deputy Chairman, Chinese Medical Doctor Association MDT Special Committee Standing Committee and Youth Committee Chairman, Chinese Medical Doctor Association Colorectal Cancer Special Committee Liver Metastasis Group Deputy Chairman of the Standing Committee of the Chinese Anti-Cancer Association Gastrointestinal Stromal Tumor Committee Member of the Standing Committee and Deputy Secretary-General of the Chinese Anti-Cancer Association Cancer Drug Clinical Research Committee Member of the Colorectal Cancer Committee of the Chinese Anti-Cancer Association and Deputy Chairman of the Youth Committee Editorial Board Member of Electronic Journal of Rectal Diseases, Editorial Board Member of "Tumor Clinical and Research" References 1.
Jian Li, Jun Zhang, Xingye Wu et al.
Population and Non-Compartmental Pharmacokinetic Analysis of Ripretinib and its Active Metabolite in Chinese Patients with Gastrointestinal Stromal Tumor.
AACR 2021, LB126.
2.
Lostes-Bardaji M Julia,García-Illescas David,Valverde Claudia et al.
Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward.
[J] .
Ther Adv Med Oncol, 2021, 13 : 1758835920986498; 3.
Miettinen M, Lasota J.
Gastroenterol Clin North Am 2013;42:399-415; 4.
Rosa, K.
OncLive.
Available at: step-toward-chinese-approval-for-advancedgist.
Accessed on 3 March 2021; 5.
Li Jian,Shen Lin,The current status of and prospects in research regarding gastrointestinal stromal tumors in China.
[J] .
Cancer, 2020, null: 2048-2053.
6.
Smith Bryan D,Kaufman Michael D ,Lu Wei-Ping et al.
Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.
[J] .
Cancer Cell, 2019, 35: 738-751.
e9.
7.
Blay Jean-Yves,Serrano César,Heinrich Michael C et al.
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.
[J] .
Lancet Oncol, 2020, 21: 923-934.
Kaufman Michael D,Lu Wei-Ping et al.
Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.
[J] .
Cancer Cell, 2019, 35: 738 -751.
e9.
7.
Blay Jean-Yves,Serrano César,Heinrich Michael C et al.
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.
[J ] .
Lancet Oncol, 2020, 21: 923-934.
Kaufman Michael D,Lu Wei-Ping et al.
Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.
[J] .
Cancer Cell, 2019, 35: 738 -751.
e9.
7.
Blay Jean-Yves,Serrano César,Heinrich Michael C et al.
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.
[J ] .
Lancet Oncol, 2020, 21: 923-934.
placebo-controlled, phase 3 trial.
[J] .
Lancet Oncol, 2020, 21: 923-934.
placebo-controlled, phase 3 trial.
[J] .
Lancet Oncol, 2020, 21: 923-934.
