ABSTRACTBackground Limertinib is a novel mutant-selective and irreversible inhibitor of the epidermal growth factor receptor under development. A phase 1 open, two-period, single-sequence, self-controlled, two-part study was initiated to characterize the effects of a strong CYP3A4 inducer (rifampin) or inhibitor (itraconazole) on the pharmacokinetics of limertinib.Research design and methods Twenty-four healthy subjects in each part received a single dose of limertinib alone (160 mg, Part A; 80 mg, Part B) and with multiple doses of rifampin 600 mg once daily (Part A) or itraconazole 200 mg twice daily (Part B).Results Coadministration of rifampin decreased exposure (area under the plasma concentration-time curve from time 0 to infinity, AUC0-inf) of limertinib and its active metabolite CCB4580030 by 87.86% (geometric least-squares mean [GLSM] ratio, 12.14%; 90% confidence interval [CI], 9.89–14.92) and 66.82% (GLSM ratio, 33.18%; 90% CI, 27.72–39.72), respectively. Coadministration of itraconazole increased the AUC0-inf of limertinib by 289.8% (GLSM ratio, 389.8%; 90% CI, 334.07–454.82), but decreased that of CCB4580030 by 35.96% (GLSM ratio, 64.04%; 90% CI, 50.78–80.77).Conclusions Our study demonstrates that the concomitant use of limertinib with strong CYP3A inducers or inhibitors is not recommended. A single dose of limertinib, administered with or without rifampin or itraconazole, is generally safe and well tolerated in healthy Chinese subjects.Clinical trial registration www.clinicaltrials.gov identifier is NCT05631678.KEYWORDS: Limertinibdrug-drug interactionpharmacokineticsrifampinitraconazoleCYP 3A4EGFR-TKI Declaration of interestsM Lui and H Gui were former employees of Jiangsu Aosaikang Pharmaceutical Co., Ltd. (Nanjing, China). This study received funding from Jiangsu Aosaikang Pharmaceutical Co., Ltd. (Nanjing, China). The funder had the following involvement with the study including study design, data analysis and preparation of the manuscript.The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Data availability statementThe data that support the findings of this study are available from the corresponding author upon reasonable request.Ethics statementThe studies were conducted in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonisation, and any applicable national and local laws and regulations. The study protocols and informed consent documents were approved by the institutional review board (IRB) of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School (IRB#: 2022–127). Informed consent was obtained from all individual participants included in the study.Author contributionsB Cao, H Guo and J Li designed the research. All authors participated in the research and reviewed the manuscript. B Cao, L Huang and M Liu analyzed the data. B Cao and H Guo contributed to protocol development and manuscript preparation.AcknowledgmentsThe authors would like to thank all subjects and their families. Plasma samples were analysed by Jiangsu Wanlue Pharmaceutical Technology Co., Ltd. and statistical analysis was performed by Shanghai Renzhi Data Technology Co., Ltd.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2023.2260738Additional informationFundingThis manuscript was funded by Jiangsu Aosaikang Pharmaceutical Co., Ltd. (Nanjing, China), and also supported partly by China National Major Project for New Drug Innovation [2017ZX09304015] and funding for Clinical Trials from Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School [2022-LCYJ-PY-19].
Abstract Non-genotoxic reactivation of p53 by MDM2 inhibitors represents a promising therapeutic strategy for tumors with wild-type TP53, particularly tumors harboring MDM2 amplification. MDM2 controls p53 levels by targeting it for degradation, while disruption of the MDM2-p53 interaction causes rapid accumulation of p53 and activation of the p53 pathway. We examined the efficacy of the small molecule MDM2 inhibitor KRT-232, alone and in combination with radiation therapy (RT), in MDM2-amplified and/or p53 wildtype patient-derived xenograft (PDX) models of glioblastoma in vitro and in vivo. In vitro, glioblastoma PDX explant cultures showed sensitivity to KRT-232, both tumors with MDM2 amplification (GBM108 and G148) and non-amplified but TP53-wildtype lines (GBM10, GBM14, and GBM39), with IC50s ranging from 300-800 nM in FBS culture conditions. A TP53 p.F270C mutant PDX (GBM43) was inherently resistant, with IC50 >3000 nM. In the MDM2-amplified GBM108 line, KRT-232 led to a robust (5-6 fold) induction of p53-target genes p21, PUMA, and NOXA, with initiation of both apoptosis and senescence. Expression of p21 and PUMA was greater with KRT-232 in combination with RT (25-35 fold induction), while stable knock-down of p53 in GBM108 led to complete resistance to KRT-232. In contrast, GBM10 showed lower induction of p21 and PUMA (2-3 fold) and was more resistant to KRT-232. In an orthotopic GBM108 xenograft model, treatment with KRT-232 +/- RT for one week extended survival from 22 days (placebo) to 46 days (KRT-232 alone); combination KRT-232 + RT further extended survival (77 days) over RT alone (31 days). KRT-232 is an effective treatment in a subset of glioblastoma pre-clinical models alone and in combination with RT. Further studies are underway to understand the mechanisms conferring innate sensitivity or resistance to KRT-232.
Currently, the food safety problem has become a serious problem and the research aims to develop a set of traceability system which can be applied in the food. The Internet-based cloud computing solution was adopted to manage the database on the source area of the food and production time and achieve the real-time inquiry through the phone. With the test, the system can realize the online inquiry on the origin of each food. The system can effectively prevent the occurrence of food safety accident and it plays an important role for the maintenance of food safety.
In this study, to investigate clinical characteristics, response, outcome, and prognosis of peripheral blood stem cell transplantation (PBSCT) for patients with peripheral T-cell lymphoma (PTCL).This study retrospectively analyzed the efficacy of PBSCT in 38 patients with PTCL. Kaplan-Meier methods were used in survival analysis, and the Cox regression model was applied in multivariate analysis. There were ten clinical parameters were analyzed.The 2-year overall survival (OS) was 46%, and the 5-year OS was 34% after a median follow-up of 40 months. The patients who received allogeneic PBSCT (allo-PBSCT) had a higher nonrelapse mortality than autologous PBSCT (auto-PBSCT), but they could achieve a longer-term disease-free survival in the former, which OS could achieve 40%. Survival analysis with Kaplan-Meier method showed the pretransplant disease status, B symptoms, serum lactate dehydrogenase (LDH) in early (>275 U/L), Eastern Cooperative Oncology Group (ECOG) score (>1), prognostic index for PTCL score (>2) were all prognostic factors for posttransplant OS. Pretransplant disease status is the only prognostic factor for allo-PBSCT.The key was to reducing transplant-related mortality of allo-PBSCT by reduced-intensity conditioning. Factors such as level of early serum LDH, extranodal involvement, B symptoms, ECOG score, Ann Arbor stage, and pretransplant disease status were all related to the prognosis of patients treated with PBSCT. Allo-PBSCT maybe suggested as the first line therapy for late-stage PTCL patients who could reach treatment remission before transplantation.
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