Evaluation of drug–drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects
Abstract SKLB1028 is a novel multi‐target protein kinase inhibitor under investigation for the treatment of FLT3‐ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug–drug interaction clinical studies were performed to investigate the effect...
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| Format: | Article |
| Language: | English |
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Wiley
2024-11-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.70063 |
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| author | Jingcheng Chen Jingxuan Wu Nini Guo Yuqin Song Lijun Li Bingyan Wang Jiangshuo Li Mengyu Hou Hang Yin Meijuan Zhang Yanhong Kong Xiaofang Wu Ran Li Le Wu Qiannan Gao Ruihua Dong |
| author_facet | Jingcheng Chen Jingxuan Wu Nini Guo Yuqin Song Lijun Li Bingyan Wang Jiangshuo Li Mengyu Hou Hang Yin Meijuan Zhang Yanhong Kong Xiaofang Wu Ran Li Le Wu Qiannan Gao Ruihua Dong |
| author_sort | Jingcheng Chen |
| collection | DOAJ |
| description | Abstract SKLB1028 is a novel multi‐target protein kinase inhibitor under investigation for the treatment of FLT3‐ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug–drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co‐administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co‐administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies. |
| format | Article |
| id | doaj-art-08b1e014c7234a049255802db29a33b6 |
| institution | Kabale University |
| issn | 1752-8054 1752-8062 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj-art-08b1e014c7234a049255802db29a33b62024-11-26T07:10:37ZengWileyClinical and Translational Science1752-80541752-80622024-11-011711n/an/a10.1111/cts.70063Evaluation of drug–drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjectsJingcheng Chen0Jingxuan Wu1Nini Guo2Yuqin Song3Lijun Li4Bingyan Wang5Jiangshuo Li6Mengyu Hou7Hang Yin8Meijuan Zhang9Yanhong Kong10Xiaofang Wu11Ran Li12Le Wu13Qiannan Gao14Ruihua Dong15Beijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaCSPC Zhongqi Pharmaceutical Technology (SJZ) Co., Ltd. Shijiazhuang Hebei Province ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaBeijing Friendship Hospital Capital Medical University Beijing ChinaAbstract SKLB1028 is a novel multi‐target protein kinase inhibitor under investigation for the treatment of FLT3‐ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug–drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co‐administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co‐administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.https://doi.org/10.1111/cts.70063 |
| spellingShingle | Jingcheng Chen Jingxuan Wu Nini Guo Yuqin Song Lijun Li Bingyan Wang Jiangshuo Li Mengyu Hou Hang Yin Meijuan Zhang Yanhong Kong Xiaofang Wu Ran Li Le Wu Qiannan Gao Ruihua Dong Evaluation of drug–drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects Clinical and Translational Science |
| title | Evaluation of drug–drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects |
| title_full | Evaluation of drug–drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects |
| title_fullStr | Evaluation of drug–drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects |
| title_full_unstemmed | Evaluation of drug–drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects |
| title_short | Evaluation of drug–drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects |
| title_sort | evaluation of drug drug interactions of a novel potent flt3 inhibitor sklb1028 in healthy subjects |
| url | https://doi.org/10.1111/cts.70063 |
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