Masato Fukae, James Rogers, Ramon Garcia, Masaya Tachibana, Takako Shimizu
{"title":"贝叶斯稀疏回归用于疗效和安全性终点的暴露-反应分析,以证明伐麦司他治疗成人T细胞白血病/淋巴瘤的临床剂量是合理的。","authors":"Masato Fukae, James Rogers, Ramon Garcia, Masaya Tachibana, Takako Shimizu","doi":"10.1002/psp4.13203","DOIUrl":null,"url":null,"abstract":"<p><p>Valemetostat is an oral inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 approved in Japan for the treatment of adult T-cell leukemia/lymphoma (ATLL). To support the approved daily dose of 200 mg and inform dose adjustments in patients with ATLL, Bayesian exposure-response analyses were conducted using data from two clinical trials. The analyses included two efficacy endpoints, overall response by central and investigator assessments in patients with ATLL (n = 38, 150-200 mg), and six safety endpoints in patients with non-Hodgkin lymphoma (n = 102, 150-300 mg), which included grade ≥3 laboratory values for anemia, absolute neutrophil count decreased, and platelet count decreased; any grade ≥3 treatment-emergent adverse event (TEAE); and dose reductions and dose interruptions due to TEAEs. A slightly positive relationship was observed between unbound exposure and efficacy endpoints. A steeper relationship was observed in safety endpoints, compared with efficacy. Candidate covariate effects, except intercepts of the baseline laboratory values, were regularized via spike and slab priors in a Bayesian framework; only the laboratory values for corresponding hematologic TEAEs were shown to be of substantial impact. The target exposure range was established by defining a modified region of practical equivalence (184-887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter-individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Bayesian sparse regression for exposure-response analyses of efficacy and safety endpoints to justify the clinical dose of valemetostat for adult T-cell leukemia/lymphoma.\",\"authors\":\"Masato Fukae, James Rogers, Ramon Garcia, Masaya Tachibana, Takako Shimizu\",\"doi\":\"10.1002/psp4.13203\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Valemetostat is an oral inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 approved in Japan for the treatment of adult T-cell leukemia/lymphoma (ATLL). To support the approved daily dose of 200 mg and inform dose adjustments in patients with ATLL, Bayesian exposure-response analyses were conducted using data from two clinical trials. The analyses included two efficacy endpoints, overall response by central and investigator assessments in patients with ATLL (n = 38, 150-200 mg), and six safety endpoints in patients with non-Hodgkin lymphoma (n = 102, 150-300 mg), which included grade ≥3 laboratory values for anemia, absolute neutrophil count decreased, and platelet count decreased; any grade ≥3 treatment-emergent adverse event (TEAE); and dose reductions and dose interruptions due to TEAEs. A slightly positive relationship was observed between unbound exposure and efficacy endpoints. A steeper relationship was observed in safety endpoints, compared with efficacy. Candidate covariate effects, except intercepts of the baseline laboratory values, were regularized via spike and slab priors in a Bayesian framework; only the laboratory values for corresponding hematologic TEAEs were shown to be of substantial impact. The target exposure range was established by defining a modified region of practical equivalence (184-887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter-individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL.</p>\",\"PeriodicalId\":10774,\"journal\":{\"name\":\"CPT: Pharmacometrics & Systems Pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-08-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CPT: Pharmacometrics & Systems Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/psp4.13203\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CPT: Pharmacometrics & Systems Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/psp4.13203","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Bayesian sparse regression for exposure-response analyses of efficacy and safety endpoints to justify the clinical dose of valemetostat for adult T-cell leukemia/lymphoma.
Valemetostat is an oral inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 approved in Japan for the treatment of adult T-cell leukemia/lymphoma (ATLL). To support the approved daily dose of 200 mg and inform dose adjustments in patients with ATLL, Bayesian exposure-response analyses were conducted using data from two clinical trials. The analyses included two efficacy endpoints, overall response by central and investigator assessments in patients with ATLL (n = 38, 150-200 mg), and six safety endpoints in patients with non-Hodgkin lymphoma (n = 102, 150-300 mg), which included grade ≥3 laboratory values for anemia, absolute neutrophil count decreased, and platelet count decreased; any grade ≥3 treatment-emergent adverse event (TEAE); and dose reductions and dose interruptions due to TEAEs. A slightly positive relationship was observed between unbound exposure and efficacy endpoints. A steeper relationship was observed in safety endpoints, compared with efficacy. Candidate covariate effects, except intercepts of the baseline laboratory values, were regularized via spike and slab priors in a Bayesian framework; only the laboratory values for corresponding hematologic TEAEs were shown to be of substantial impact. The target exposure range was established by defining a modified region of practical equivalence (184-887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter-individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL.