Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors
Background: ORIN1001, a first-in-class oral IRE1-α endoribonuclease inhibitor to block the activation of XBP1, is currently in clinical development for inhibiting tumor growth and enhancing the effect of chemical or targeted therapy. Early establishment of a population pharmacokinetic (PopPK) model...
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| Format: | Article |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1322557/full |
| _version_ | 1827330839450484736 |
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| author | Xiaoqing Li Yunhai Bo Qingping Zeng Lei Diao Stephanie Greene John Patterson Lu Liu Fen Yang |
| author_facet | Xiaoqing Li Yunhai Bo Qingping Zeng Lei Diao Stephanie Greene John Patterson Lu Liu Fen Yang |
| author_sort | Xiaoqing Li |
| collection | DOAJ |
| description | Background: ORIN1001, a first-in-class oral IRE1-α endoribonuclease inhibitor to block the activation of XBP1, is currently in clinical development for inhibiting tumor growth and enhancing the effect of chemical or targeted therapy. Early establishment of a population pharmacokinetic (PopPK) model could characterize the pharmacokinetics (PK) of ORIN1001 and evaluate the effects of individual-specific factors on PK, which will facilitate the future development of this investigational drug.Methods: Non-linear mixed effect model was constructed by Phoenix NLME software, utilizing the information from Chinese patients with advanced solid tumors in a phase I clinical trial (Register No. NCT05154201). Statistically significant PK covariates were screened out by a stepwise process. The final model, after validating by the goodness-of-fit plots, non-parametric bootstrap, visual predictive check and test of normalized prediction distribution errors, was further applied to simulate and evaluate the impact of covariates on ORIN1001 exposure at steady state up to 900 mg per day as a single agent.Results: A two-compartment model with first-order absorption (with lag-time)/elimination was selected as the best structural model. Total bilirubin (TBIL) and lean body weight (LBW) were considered as the statistically significant covariates on clearance (CL/F) of ORIN1001. They were also confirmed to exert clinically significant effects on ORIN1001 steady-state exposure after model simulation. The necessity of dose adjustments based on these two covariates remains to be validated in a larger population.Conclusion: The first PopPK model of ORIN1001 was successfully constructed, which may provide some important references for future research. |
| first_indexed | 2024-03-07T16:23:13Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-07T16:23:13Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-f807ce6e694648adacfed803dbdf30742024-03-04T04:29:35ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-03-011510.3389/fphar.2024.13225571322557Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumorsXiaoqing Li0Yunhai Bo1Qingping Zeng2Lei Diao3Stephanie Greene4John Patterson5Lu Liu6Fen Yang7Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), National Drug Clinical Trial Center, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), National Drug Clinical Trial Center, Peking University Cancer Hospital and Institute, Beijing, ChinaFosun Orinove, Inc., Suzhou, ChinaShanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, ChinaFosun Orinove, Inc., Suzhou, ChinaFosun Orinove, Inc., Suzhou, ChinaShanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), National Drug Clinical Trial Center, Peking University Cancer Hospital and Institute, Beijing, ChinaBackground: ORIN1001, a first-in-class oral IRE1-α endoribonuclease inhibitor to block the activation of XBP1, is currently in clinical development for inhibiting tumor growth and enhancing the effect of chemical or targeted therapy. Early establishment of a population pharmacokinetic (PopPK) model could characterize the pharmacokinetics (PK) of ORIN1001 and evaluate the effects of individual-specific factors on PK, which will facilitate the future development of this investigational drug.Methods: Non-linear mixed effect model was constructed by Phoenix NLME software, utilizing the information from Chinese patients with advanced solid tumors in a phase I clinical trial (Register No. NCT05154201). Statistically significant PK covariates were screened out by a stepwise process. The final model, after validating by the goodness-of-fit plots, non-parametric bootstrap, visual predictive check and test of normalized prediction distribution errors, was further applied to simulate and evaluate the impact of covariates on ORIN1001 exposure at steady state up to 900 mg per day as a single agent.Results: A two-compartment model with first-order absorption (with lag-time)/elimination was selected as the best structural model. Total bilirubin (TBIL) and lean body weight (LBW) were considered as the statistically significant covariates on clearance (CL/F) of ORIN1001. They were also confirmed to exert clinically significant effects on ORIN1001 steady-state exposure after model simulation. The necessity of dose adjustments based on these two covariates remains to be validated in a larger population.Conclusion: The first PopPK model of ORIN1001 was successfully constructed, which may provide some important references for future research.https://www.frontiersin.org/articles/10.3389/fphar.2024.1322557/fullpopulation pharmacokinetic modelORIN1001model constructionmodel evaluationmodel simulation |
| spellingShingle | Xiaoqing Li Yunhai Bo Qingping Zeng Lei Diao Stephanie Greene John Patterson Lu Liu Fen Yang Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors Frontiers in Pharmacology population pharmacokinetic model ORIN1001 model construction model evaluation model simulation |
| title | Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors |
| title_full | Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors |
| title_fullStr | Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors |
| title_full_unstemmed | Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors |
| title_short | Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors |
| title_sort | population pharmacokinetic model for oral orin1001 in chinese patients with advanced solid tumors |
| topic | population pharmacokinetic model ORIN1001 model construction model evaluation model simulation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1322557/full |
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