Максим Рильський у світлі теорії та практики перекладу

У запропонованій статті проаналізовано актуальні проблеми теорії і практики перекладу у світлі завдань сучасного перекладознавства, зокрема, об’єктом аналізу є переклади М. Т. Рильським визначних творів зі світової літературної скарбниці.В данной статье анализируются актуальные проблемы теории и практики перевода в соответствии с задачами современного переводоведения, в частности, объектом анализа выступают переводы М. Т. Рыльским выдающихся произведений мировой литературы.In the offered article the issues of the day of theory and practice of translation are analysed in the light of tasks of modern translation theory in particular as an object of analysis translations of Maksym Rylski come forward prominent works from a world literary treasury

Two-stage model-based design of cancer phase I dose escalation trials: evaluation using the phase I program of barasertib (AZD1152)

Introduction Modeling and simulation of pharmacokinetics and pharmacodynamics has previously been shown to be potentially useful in designing Phase I programs of novel anti-cancer agents that show hematological toxicity. In this analysis, a two-stage model-based trial design was evaluated retrospectively using data from the Phase I program with the aurora kinase inhibitor barasertib. Methods Data from two Phase I trials and four regimens were used (n = 79). Using barasertib-hydroxy QPA plasma concentrations and neutrophil count data from only study 1A, a PKPD model was developed and subsequently used to predict the MTD and a safe starting dose for the other trials. Results The PKPD model based on data from the first study adequately described the time course of neutrophil count fluctuation. The two-stage model-based design provided safe starting doses for subsequent phase I trials for barasertib. Predicted safe starting dose levels were higher than those used in two subsequent trials, but lower than used in the other trial. Discussion The two-stage approach could have been applied safely to define starting doses for alternative dosing strategies with barasertib. The limited improvement in efficiency for the phase I program of barasertib may have been due to the fact that starting doses for the studied phase I trials were already nearly optimal. Conclusion Application of the two-stage model-based trial design in Phase I programs with novel anti-cancer drugs that cause haematological toxicity is feasible, safe, and may lead to a reduction in the number of patient treated at sub-therapeutic dose-levels

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921

Pediatric patients; Intolerant; Chronic myeloid leukemiaPacientes pediátricos; Intolerantes; Leucemia mieloide crónicaPacients pediàtrics; Intolerants; Leucèmia mieloide crònicaPurpose Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. Patients and Methods In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. Results Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 μg h/mL, 2.52 μg h/mL, and 2.66 μg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. Conclusion Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.Sponsorship for the study was provided by Erasmus MC/Sophia Children's Hospital, Department of Pediatrics, Rotterdam, the Netherlands

Two-stage model-based clinical trial design to optimize phase I development of novel anticancer agents

Background The phase I program of anticancer agents usually consists of multiple dose escalation studies to select a safe dose for various administration schedules. We hypothesized that pharmacokinetic and pharmacodynamic (PK–PD) modeling of an initial phase I study (stage 1) can be used for selection of an optimal starting dose for subsequent studies (stage 2) and that a post-hoc PK–PD analysis enhances the selection of a recommended dose for phase II evaluation. The aim of this analysis was to demonstrate that this two-stage model-based design, which does not interfere in the conduct of trials, is safe, efficient and effective. Methods PK and PD data of dose escalation studies were simulated for nine compounds and for five administration regimens (stage 1) for drugs with neutropenia as dose-limiting toxicity. PK–PD models were developed for each simulated study and were used to determine a starting dose for additional phase I studies (stage 2). The model-based design was compared to a conventional study design regarding safety (number of dose-limiting toxicities (DLTs)), efficiency (number of patients treated with a dose below the recommended dose) and effectiveness (precision of dose selection). Retrospective data of the investigational anticancer drug indisulam were used to show the applicability of the model-based design. Results The model-based design was as safe as the conventional design (median number of DLTs = 3) and resulted in a reduction of the number of patients who were treated with a dose below the recommended dose (−27%, power 89%). A post-hoc model-based determination of the recommended dose for future phase II studies was more precise than the conventional selection of the recommended dose (root mean squared error 8.3% versus 30%). Conclusions A two-stage model-based phase I design is safe for anticancer agents with dose-limiting myelosuppression and may enhance the efficiency of dose escalation studies by reducing the number of patients treated with a dose below the recommended dose and by increasing the precision of dose selection for phase II evaluation

Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Although kinase inhibitors (KI) frequently portray large interpatient variability, a ‘one size fits all’ regimen is still often used. In the meantime, relationships between exposure-response and exposure-toxicity have been established for several KIs, so this regimen could lead to unnecessary toxicity and suboptimal efficacy. Dose adjustments based on measured systemic pharmacokinetic levels—i.e., therapeutic drug monitoring (TDM)—could therefore improve treatment efficacy and reduce the incidence of toxicities. Therefore, the aim of this comprehensive review is to give an overview of the available evidence for TDM for the 77 FDA/EMA kinase inhibitors currently approved (as of July 1st, 2023) used in hematology and oncology. We elaborate on exposure-response and exposure-toxicity relationships for these kinase inhibitors and provide practical recommendations for TDM and discuss corresponding pharmacokinetic targets when possible.</p

The impact of structural uncertainty on cost-effectiveness models for adjuvant endocrine breast cancer treatments: The need for disease-specific model standardization and improved guidance

__Abstract__ Introduction: Structural uncertainty relates to differences in model structure and parameterization. For many published health economic analyses in oncology, substantial differences in model structure exist, leading to differences in analysis outcomes and potentially impacting decision-making processes. The objectives of this analysis were (1) to identify differences in model structure and parameterization for cost-effectiveness analyses (CEAs) comparing tamoxifen and anastrazole for adjuvant breast cancer (ABC) treatment; and (2) to quantify the impact of these differences on analysis outcome metrics. Methods: The analysis consisted of four steps: (1) review of the literature for identification of eligible CEAs; (2) definition and implementation of a base model structure, which included the core structural components for all identified CEAs; (3) definition and implementation of changes or additions in the base model structure or parameterization; and (4) quantification of the impact of changes in model structure or parameterizations on the analysis outcome metrics life-years gained (LYG), incremental costs (IC) and the incremental cost-effectiveness ratio (ICER). Results: Eleven CEA analyses comparing anastrazole and tamoxifen as ABC treatment were identified. The base model consisted of the following health states: (1) on treatment; (2) off treatment; (3) local recurrence; (4) metastatic disease; (5) death due to breast cancer; and (6) death due to other causes. The base model estimates of anastrazole versus tamoxifen for the LYG, IC and ICER were 0.263 years, €3,647 and €13,868/LYG, respectively. In the published models that were evaluated, differences in model structure included the addition of different recurrence health states, and associated transition rates were identified. Differences in parameterization were related to the incidences of recurrence, local recurrence to metastatic disease, and metastatic disease to death. The separate impact of these model components on the LYG ranged from 0.207 to 0.356 years, while incremental costs ranged from €3,490 to €3,714 and ICERs ranged from €9,804/LYG to €17,966/LYG. When we re-analyzed the published CEAs in our framework by including their respective model properties, the LYG ranged from 0.207 to 0.383 years, IC ranged from €3,556 to €3,731 and ICERs ranged from €9,683/LYG to €17,570/LYG. Conclusion:

Therapeutic drug monitoring of oral targeted antineoplastic drugs

Purpose This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window

Особенности промышленного развития монофункциональных городов Донецкой области

Рассмотрены особенности промышленности моноотраслевых городов Донецкой области. Предлагаются мероприятия по решению проблем их социально-экономического развития.Розглянуто особливості промисловості моногалузевих міст Донецької області. Пропонуються заходи щодо вирішення проблем їх соціально-економічного розвитку.The paper describes the features of the industry in mono-branch cities of Donetsk region. The measures are offered to solve the problems concerning their socio-economic development

О некоторых аспектах проблемы формирования рынка труда в Украине и в Крыму

В статье дан анализ современного состояния рынка труда в Украине и в Крыму, выявлены причины и особенности безработицы, определены задачи государства в этой связи, предложены мероприятия по их разрешению.Про деякі аспекти проблеми формування ринку праці в Україні і в Криму. У статті даний аналіз сучасного стану ринку праці в Україні й у Криму, виявлено причини й особливості безробіття, визначені завдання держави в цьому зв'язку, запропоновані заходи щодо їхнього вирішення.In article the analysis of a modern condition of a labour market in Ukraine and in Crimea is given, the reasons and features of unemployment are revealed, problems of the state in this connection are determined, actions under their sanction are offered