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Summary plot of the global Desirability Index used for optimal study design versus key variables shown as x-axes labels. Dose maximal: highest mg/kg dose envisaged; LLOQ: lower limit of quantification of OKZ PK assay; upper CRP/lower CRP: limits of baseline CRP range envisaged in 0.1 µg/ml. Red figures directly above the x-axes labels indicate the value of the respective variable which gave rise to the desirability index value shown on the y-axis label. (a) Desirability Index for LLOQ of PK assay equal to 0.03 µg/ml. (b) Desirability Index for LLOQ of PK assay equal to 0.1 µg/ml. LLOQ, lower limit of quantification; OKZ, olokizumab.
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The first‐in‐patient study for olokizumab (OKZ) employed model‐based, optimal design and adaptive execution to define the concentration–C‐reactive protein (CRP) suppression response. Modeling and exploratory statistics activities involved: reverse engineering of first‐in‐class (tocilizumab) pharmacokinetic/pharmacodynamic (PK/PD) models, adaptation...
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Citations
... Это первый прямой антагонист ИЛ-6 [10]. Он показал свою эффективность и безопасность в терапии больных РА на всех этапах клинических исследований, проведенных как в Российской Федерации [11][12][13], так и за рубежом [14][15][16][17]. При этом в отечественной литературе его применение в реальной клинической прак тике базируются лишь на описании отдельных клинических случаев [18], а публикации об его эффективности в отношении исходов, сообщаемым самим пациентом, а также о влиянии на психоэмоциональный статус основаны на данных рандомизированного плацебо-контро лируемемого многоцентрового исследования III фазы (CREDO 1) [19]. ...
... Высокая эффективность и безопасность применения ОКЗ у больных РА подтверждена в рандомизированных плацебо-контролируемых исследованиях в рамках программы CREDO [11][12][13][14][15][16][17]. ...
The aim of the study was to evaluate in real clinical practice the effectiveness of therapy with an interleukin-6 inhibitor (olokizumab) in patients with rheumatoid arthritis (RA) in terms of clinical and laboratory activity of the disease, as well as patient-reported outcomes (PROs). Material and methods . 10 patients with a reliable diagnosis of RA were examined: the average age of the patients was 45.70±17.9 years, the duration of the disease was 9.0 (3.0; 12.0) years. Patients were with moderate or high disease activity: DAS28-ESR – 5.13 (4.34; 5.80) points; CDAI – 30.00 (24.00; 35.00); SDAI – 31.86 (24.36; 38,59). All patients were prescribed treatment with olokizumab (OKZ) at a dose of 64 mg subcutaneously every 4 weeks against the background of therapy with methotrexate, leflunomide, non-steroidal anti-inflammatory drugs and glucocorticoids (GC) (up to 10 mg/day in terms of prednisolone). Three patients had previously received tocilizumab (intravenously once a month at a dose of 8 mg/kg), the administration of which was discontinued for administrative reasons 6–12 months before the appointment of OKZ. The results of treatment were assessed by the dynamics of clinical, laboratory parameters (DAS28-ESR, SDAI, СDAI, CRP, ESR, IgM RF, ACCP) and outcomes assessed by the patients themselves (PROs): HAQ-DI index, general assessment of the health status of patients (OSZB) according to VAS, pain according to VAS; scales FACIT, SF-36. As psychometric methods, the questionnaire “Type of attitude towards the disease (TOBOL)”, the Hospital Anxiety and Depression Scale (HADS), and the Toronto Alexithymic Scale (TAS-26) were used. Observation was carried out before treatment, after 3 and 6 months of therapy. Results . Against the background of OKZ therapy, after 3 and 6 months, compared with the baseline, there was a significant decrease in the clinical indices of RA activity: DAS28-ESR – 5.13 (4.34; 5.80), 3.53 (2.83; 4.26) and 3.48 (2.8; 4.10) points respectively; CDAI – 30.00 (24.00; 35.00), 11.00 (6.0; 16.00) and 10.0 (5.0; 15.0) points respectively; SDAI – 31.86 (24.36; 38.59), 11.05 (6.07; 16.07) and 10.17 (7.02; 15.02) points respectively; CRP – 14.30 (7.00; 24.70), 0.70 (0.40; 0.90) and 0.65 (0.20; 3.0) mg/l respectively. No significant dynamics of ESR, RF IgM and ACCP was noted. After 3 and 6 months of treatment with OKZ, there was a significant decrease in OSZB and pain severity according to the VAS scale, and an improvement in the functional state of patients was observed according to the HAQ-DI questionnaire of fatigue indicators (FACIT-F) (p<0.05). The physical component of the SF-36 scale increased significantly only by the 6th month of therapy (p<0.01), while the mental component did not undergo significant changes (p>0.05). In the process of treatment of OKZ, the attitude of patients to the disease changed from the ergopathic, neurasthenic and sensitive components in the TOBOL profile, before it began, then by its end, the dominant ones were harmonious, ergopathic and sensitive profiles. In addition, starting from the 3rd month of treatment in patients with RA, an adaptive response to the disease prevailed. A decrease in the level of anxiety was revealed, compared with the baseline, after 3 and 6 months of observation, depression indicators did not change significantly. Conclusion . In general, the results of this study indicate the effectiveness of ICD in RA, not only in terms of reducing the clinical and laboratory activity of the disease, but also in terms of outcomes reported by the patient himself, characterizing the quality of life and the psycho-emotional state of patients.
... В России применению ОКЗ при РА посвящены описание отдельных клинических случаев, отрытые исследования и анализ его эффективности после перевода по немедицинским показаниям (административного перевода) с других ГИБП (ритуксимаб, ТЦЗ, САР) в период пандемии COVID-19 [13][14][15][16]. Данные, касающиеся оценки динамики ИЛ-6 на фоне лечения ОКЗ у пациентов с РА, немногочисленны [17,18]. ...
The aim of the study was to investigate the dynamics of clinical and laboratory parameters of inflammatory disease activity and cytokines in patients with rheumatoid arthritis (RA) against the background of olokizumab (OKZ) treatment. Materials and methods. Ten patients with a reliable diagnosis of RA were examined: patients’ age was 46.00 (30.00; 60.00) years, duration of disease was 9.0 (3.0; 12,0) years. All patients had moderate to high disease activity: DAS28-ESR (Disease Activity Score 28 with Erythrocyte Sedimentation Rate) – 513 (4.34; 5,80); CDAI (Clinical Disease Activity Index) – 30.00 (24.00; 35.00); SDAI (Simplified Disease Activity Index) – 31.86 (24.36; 38.59). All patients were treated with OKZ at a dose of 64 mg subcutaneously every 4 weeks on the background of therapy with methotrexate, leflunomide, nonsteroidal anti-inflammatory drugs, and glucocorticoids. Observations were performed before treatment and after 3, 6 months of therapy. Serum levels of 15 cytokines: interleukin (IL) 1β, IL-4, IL-6, tumor necrosis factor α (TNF-α), interferon (INF) γ, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, sCD40L, – were examined using multiplex xMAR technology. Results. After 3 and 6 months of OKZ therapy, there was a significant decrease in DAS28-ESR of 3.53 (2.83; 4.26) and 3.48 (2.8; 4.10); CDAI – 11.00 (6.0; 16.00) and 10.0 (5.0; 15.0); SDAI – 10.0 (5.0; 15.0) and 10.17 (7.02; 15.02); C-reactive protein (CRP) concentrations (initial – 14.30 (7.00; 24.70) mg/l, after 3 months – 0.70 (0.40; 0.90) mg/l and after 6 months – 0.65 (0.20; 3.00) mg/l). After 3 months of treatment we found an increase in IL-6 concentration (initial – 1.89 (1.61; 2.33) pg/ml and 89.98 (35.09; 165.84) pg/ml; p<0.01), after 6 months – its level decreased to 44.88 (5.25; 80.90) pg/ml without reaching, however, the initial values (p<0.05). Against the background of OCZ, after 3 months of treatment there was an increase in IL-25 concentration (p<0.01), and after 6 months of therapy – TNF-α (p<0.05). Conclusion. The use of OKZ leads to an increase in the concentration of total IL-6 in the blood serum of RA patients, while the clinical and laboratory activity of the disease decreases.
... Olokizumab successfully passed through phase I of a randomized clinical trial, where the pharmacogenetic, pharmacokinetic, and immunogenic properties of the drug were evaluated in healthy volunteers [8]. Further, its dosage was investigated in RA patients with a similar study of tocilizumab taken as an initial model [9]. Phase II of the study was performed on 119 Asian patients and revealed a significantly more frequent response to olokizumab in comparison with placebo in patients with severe RA who were resistant to TNF inhibitors [10]. ...
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease and its treatment is an urgent problem of rheumatology. Olokizumab (OKZ) is a new humanized monoclonal antibody targeting IL-6 and is one of the few promising drugs for RA therapy. One-hundred-and-twenty-five DNA samples from Russian patients with RA, treated with olokizumab, were genotyped with an NGS panel containing 60 single nucleotide polymorphisms (SNPs) and the whole coding sequences of IL6, IL6R, TNFRSF1A, CTLA4, IL10, IL23R, and PADI4; and by RT-PCR for HLA-DRB1 and HLA-B. Associations of polymorphic variants with olokizumab efficacy according to the scores ACR20, ACR50, and DAS28-CRP were determined. We analyzed the obtained data by using logistic regression, ROC curves, and multivariate ANOVA. A high predictive value of the response to olokizumab therapy at 24 weeks was found for the combination of HLA-DRB1*04 and HLA-B*27 alleles with SNPs located in non-HLA genes (IL1B, IL17A, PADI4, DHODH, GLCCI1, IL23R, and TNFAIP3), and clinical characteristics (age, RA duration, and intensity) according to ACR20. Thus, the comprehensive assessment of polymorphic variants of HLA and non-HLA genes considering population characteristics in combination with clinical parameters allows for the elaboration of an RA prognostic panel.
... В настоящее время для лечения РА разработан широкий спектр инновационных генно-инженерных биологических препаратов (ГИБП) [10], среди которых особый интерес представляют моноклональные антитела против рецептора (Р) интерлейкина-6 (ИЛ-6) или самого ИЛ-6 [11][12][13]. Олокизумаб (OКЗ) -гуманизированное моноклональное антитело (IgG4 каппа), специфически нейтрализующее ИЛ-6, фармакокинетические характеристики, эффективность и безопасность которого при РА были доказаны в рандомизированных контролируемых исследованиях (РКИ) фазы I и в двух клинических исследованиях фазы II [14][15][16][17]. В РКИ фазы III CREDO 1 (NCT02760368) изучалась эффективность подкожной формы препарата ОКЗ в дозе 64 мг каждые 2 недели (к2н) и каждые 4 недели (к4н) у пациентов со среднетяжелым и тяжелым РА, недостаточно контролируемым терапией метотрексатом (МТ). ...
... является научным советником компании «Р-Фарм». (13,92); боль по ВАШ -20,77% (9,66); FACIТ-F -19,31% (7,41); SF-36 (физический компонент) -19,29% (7,39); SF-36 (психический компонент) -15,11% (3,19); Разность группы ОКЗ 64 мг к2н с группой плацебо (97,5% ДИ): боль по ВАШ -25,17 (14,89); ООАЗП -24,48% (13,99); HAQ-DI -19,58% (8,(29)(30)(31)63); FACIТ-F -18,88% (7,96); SF-36 (физический компонент) -27,97% (17,96); SF-36 (психический компонент) -9,09% (-2,60-21,14 (9,62); FACIТ-F -17,84% (6,81); боль по ВАШ -13,73% (3,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)76); SF-36 (психический компонент) -16,45% (5,49); SF-36 (физический компонент) -12,28% (0, 37). Разность группы ОКЗ 64 мг к2н с группой плацебо (97,5% ДИ): ООАЗП -16,89% (6,32); боль по ВАШ - 14,19% (3,68-25,13); FACIТ-F -13,99% (2,86); HAQ-DI -11,89% (0, 85); SF-36 (физический компонент) - 11,19% (-0,44-23,25); SF-36 (психический компонент) -6,29% (-5,24-18,06 ...
... является научным советником компании «Р-Фарм». (13,92); боль по ВАШ -20,77% (9,66); FACIТ-F -19,31% (7,41); SF-36 (физический компонент) -19,29% (7,39); SF-36 (психический компонент) -15,11% (3,19); Разность группы ОКЗ 64 мг к2н с группой плацебо (97,5% ДИ): боль по ВАШ -25,17 (14,89); ООАЗП -24,48% (13,99); HAQ-DI -19,58% (8,(29)(30)(31)63); FACIТ-F -18,88% (7,96); SF-36 (физический компонент) -27,97% (17,96); SF-36 (психический компонент) -9,09% (-2,60-21,14 (9,62); FACIТ-F -17,84% (6,81); боль по ВАШ -13,73% (3,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)76); SF-36 (психический компонент) -16,45% (5,49); SF-36 (физический компонент) -12,28% (0, 37). Разность группы ОКЗ 64 мг к2н с группой плацебо (97,5% ДИ): ООАЗП -16,89% (6,32); боль по ВАШ - 14,19% (3,68-25,13); FACIТ-F -13,99% (2,86); HAQ-DI -11,89% (0, 85); SF-36 (физический компонент) - 11,19% (-0,44-23,25); SF-36 (психический компонент) -6,29% (-5,24-18,06 ...
Background. Olokizumab is a new interleukin-6 (IL-6) inhibitor that has demonstrated good efficacy and safety for the treatment of adult patients with moderate to high-grade activity of rheumatoid arthritis in combination with methotrexate with insufficient efficacy of methotrexate monotherapy.Aim of the study was to evaluate the effectiveness of olokizumab in relation to the patient’s reported outcomes (PROs) based on the results obtained in the CREDO 1 phase III study.Material and methods. The study included 428 patients with rheumatoid arthritis who were randomized into 3 groups: group 1 – patients who received 64 mg of olokizumab subcutaneously every 2 weeks (q2w) (n=143); group 2 –patients who received 64 mg of olokizumab every 4 weeks (q4w) (n=142); group 3 – patients who had placebo q2w (n=143). PROs included: Health Assessment Questionnaire-Disability Index (HAQ-DI); Patient Global Assessment of Disease Activity (PtGA-VAS); Subject’s Assessment of Pain (VAS); fatigue according to the FACIT-F scale; quality of life according to the EQ-5D questionnaire; physical and mental components of the SF-36 scale. The effectiveness of olokizumab was evaluated by the dynamics of the average PROs values and the proportion of patients who reported improvement compared to the baseline level of ≥ minimum clinically important differences (MCID) for each PROs by weeks 12 and 24 of follow-up.Results. 396 patients out of 428 included completed the study. When included in the study, patients of different therapeutic groups did not differ in socio-demographic indicators, duration, activity of rheumatoid arthritis, as well as in PROs indicators. Olokizumab therapy, regardless of the dosage regimen of the drug, resulted in a significant improvement in all PROs compared to placebo after 12 weeks, and this improvement sustained until 24 weeks of therapy. The proportion of patients who reached and exceeded MCID at weeks 12 and 24 of follow-up was statistically significantly higher in both olokizumab groups compared to placebo for PtGA, VAS pain, HAQ-DI, FACIT-F. The number of patients who reached or exceeded the MCID on the physical component of the SF-36 scale at week 12 was significantly higher in both olokizumab groups, and at week 24 only in the group 2 compared to the placebo group. The mental component of SF-36 improved in a significantly higher percentage of patients in the group 2 compared to placebo group at weeks 12 and 24, while the group 1 did not significantly differ from placebo group in improving the mental component of SF-36.Conclusions. Olokizumab therapy in patients with moderate to high-grade activity of rheumatoid arthritis is associated with a significant improvement in all PROs. There was no significant difference between the dosage regimens of olokizumab.
... Beside data analysis, the usage of PK models also supports the design and realization of clinical trials. A first-inpatient study of the monoclonal anti-IL-6 antibody Olokizumab was optimized in terms of dosage and sample size by integration of pre-clinical data into a PK model (64). ...
Interleukin-6-type cytokines play important roles in the communication between cells of multicellular organisms. They are involved in the regulation of complex cellular processes such as proliferation and differentiation and act as key player during inflammation and immune response. A major challenge is to understand how these complex non-linear processes are connected and regulated. Systems biology approaches are used to tackle this challenge in an iterative process of quantitative experimental and mathematical analyses. Here we review quantitative experimental studies and systems biology approaches dealing with the function of Interleukin-6-type cytokines in physiological and pathophysiological conditions. These approaches cover the analyses of signal transduction on a cellular level up to pharmacokinetic and pharmacodynamic studies on a whole organism level.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Software and Programming Tools in Pharmaceutical Research is a detailed primer on the use for computer programs in the design and development of new drugs. Chapters offer information about different programs and computational techniques in pharmacology. The book will help readers to harness computer technologies in pharmaceutical investigations. Readers will also appreciate the pivotal role that software applications and programming tools play in revolutionizing the pharmaceutical industry.
The book includes nine structured chapters, each addressing a critical aspect of pharmaceutical research and software utilization. From an introduction to pharmaceutical informatics and computational chemistry to advanced topics like molecular modeling, data mining, and high-throughput screening, this book covers a wide range of topics.
Key Features:
- Practical Insights: Presents practical knowledge on how to effectively utilize software tools in pharmaceutical research.
- Interdisciplinary Approach: Bridges the gap between pharmaceutical science and computer science
- Cutting-Edge Topics: Covers the latest advancements in computational drug development, including data analysis and visualization techniques, drug repurposing, pharmacokinetic modelling and screening.
- Recommendations for Tools: Includes informative tables for software tools
- Referenced content: Includes scientific references for advanced readers
The book is an ideal primer for students and educators in pharmaceutical science and computational biology, providing a comprehensive foundation for this rapidly evolving field. It is also an essential resource for pharmaceutical researchers, scientists, and professionals looking to enhance their understanding of software tools and programming in drug development.
Preterm birth (PTB) and its consequences are a major public health concern as preterm delivery is the main cause of mortality and morbidity at birth. There are many causes of PTB, but inflammation is undeniably associated with the process of premature childbirth and fetal injury. At present, treatments clinically available mostly involve attempt to arrest contractions (tocolytics) but do not directly address upstream maternal inflammation on development of the fetus. One of the possible solutions may lie in the modulation of inflammatory mediators. Of the many pro-inflammatory cytokines involved in the induction of PTB, IL-6 stands out for its pleiotropic effects and its involvement in both acute and chronic inflammation. Here, we provide a detailed review of the effects of IL-6 on the timing of childbirth, its occurrence during PTB and its indissociable roles with associated fetal tissue damage.
Despite enormous success in biomedical science and technology, as well as increased research and development spending, pharmaceutical productivity has faced challenges. The success rates in drug development remain low and have shown a declining trend in the last two decades. The US FDA has also recognized the inefficiency in drug development and proposed model-based drug development (MBDD) to improve pharmaceutical productivity and decision making. Modeling and simulation provide a powerful tool to summarize and integrate information from different studies. Application of modeling and simulation can help decision making, design better studies, reduce costs, save time, and ultimately improve success rates. Beyond traditional types of modeling techniques or applications, MBDD is a paradigm that covers the entire spectrum of the drug development process. This review aims to provide an overview of modeling and simulation and their application to various drug development processes, from early discovery to preclinical and clinical stages, as well as formulation optimization. Several types of models will be discussed, and illustrative examples of their applications in the drug development process will be highlighted.
If we are to improve our low success rate and rising costs in the pharmaceutical industry, we need to use every tool available. Reverse translation can particularly inform discovery and early clinical development via appropriate quantitative integration of relevant data. This commentary reports on a crowd-sourced survey (2017) that sought to evaluate the integration of reverse translation in pharma. The results indicate that these methods are being applied, to varying degrees, across most respondents.
