RESUMO
Bioinspired molecular engineering strategies have emerged as powerful tools that significantly enhance the development of novel therapeutics, improving efficacy, specificity, and safety in disease treatment. Recent advancements have focused on identifying and utilizing disease-associated biomarkers to optimize drug activity and address challenges inherent in traditional therapeutics, such as frequent drug administrations, poor patient adherence, and increased risk of adverse effects. In this review, we provide a comprehensive overview of the latest developments in bioinspired artificial systems (BAS) that use molecular engineering to tailor therapeutic responses to drugs in the presence of disease-specific biomarkers. We examine the transition from open-loop systems, which rely on external cues, to closed-loop feedback systems capable of autonomous self-regulation in response to disease-associated biomarkers. We detail various BAS modalities designed to achieve biomarker-driven therapy, including activatable prodrug molecules, smart drug delivery platforms, autonomous artificial cells, and synthetic receptor-based cell therapies, elucidating their operational principles and practical inâ vivo applications. Finally, we discuss the current challenges and future perspectives in the advancement of BAS-enabled technology and envision that ongoing advancements toward more programmable and customizable BAS-based therapeutics will significantly enhance precision medicine.
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Biomarcadores , Sistemas de Liberação de Medicamentos , Humanos , Sistemas de Liberação de Medicamentos/métodos , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Medicina de Precisão/métodos , Células Artificiais/química , AnimaisRESUMO
Investigation of asphaltene adsorption at rock surfaces plays an important role in enhanced oil recovery (EOR) for the petroleum industry. In this work, the interaction performances of asphaltene adsorption at carbonate dolomite and calcite surfaces are investigated based on experimental and simulation insights. On the one hand, macroscopic interaction performances were investigated by spectroscopy experiments to obtain the Langmuir thermodynamic model and pseudo-second-order (PSO) kinetic model. The results indicated monolayer molecular asphaltene adsorption for both dolomite and calcite, while they showed 'slow adsorption-slow desorption' for dolomite but 'fast adsorption-fast desorption' for calcite. Meanwhile, dolomite showed a higher adsorption capacity with qm(dol 1) = 5.35 mg/g > qm(cal 1) = 1.28 mg/g and a stronger adsorption spontaneity with ΔGm(dol 1)θ = -7.76 kJ/mol < ΔGm(cal 1)θ = -4.76 kJ/mol. On the other hand, microscopic interaction performances were investigated for three asphaltene molecules by molecular dynamics simulation (MDS) with â¼8 Å distance-placing and 500 ps time-running. According to the results, dolomite showed higher system stability than calcite with a lower final energy of ΔEdol-cal = -58 kJ/mol, and archipelago asphaltene showed higher adsorption stability with the smallest equilibrium energy of Earch(dol) = -147 kJ/mol for albite and Earch(cal) = -89 kJ/mol for calcite. The model of molecular orientation and force dominance was proposed as the interaction mechanism for asphaltene adsorption, which "lie sideways" at low concentrations but "stands upright" at high concentrations. This work allows the performance investigation and mechanism illustration of asphaltene adsorption at rock surfaces, which can help gain a fundamental understanding of the EOR during reservoir exploitation.
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The prodrug mycophenolate mofetil (MMF), which is presystemically hydrolyzed into the pharmacologically active compound mycophenolic acid (MPA), has been widely used for the prophylaxis of acute allograft rejection in solid organ transplantation. However, the huge variability in the plasma concentration level makes the development of MMF drug products difficult due to the great challenge of meeting the traditional bioequivalence (BE) limits. Numerous models have been developed in the past decade to explain the variability, with the emphasis on characterizing the enterohepatic circulation. While the variability arising from systemic appearance can also contribute to the remarkable MPA variability to a great extent, it has been ignored for long for this Biopharmaceutics Classification System class 2 drug. To improve the design of the BE study for this highly variable (HV) drug, the variability of MMF pharmacokinetic (PK) profiles focusing on the absorption process was explored in a population approach. A total of 81 Chinese adult liver transplant recipients were enrolled and had their plasma concentrations of MPA and its metabolites measured by HPLC during one visit or multiple visits in a long-term MMF regimen. The population models were developed using NONMEM, and the data and the results of the model were analyzed by R. Two population PK models of MMF focusing on the absorption process were developed based on the plasma concentrations of MPA and its major metabolite 7-O-MPA-ß-glucuronide (MPAG). The MPA PK profiles were best characterized by a two-compartment disposition model with zero inter-individual variability (IIV) of elimination coefficient (K20), lag time, but considerable intra-individual variability (IAV) in the form of inter-occasion variability regarding systemic appearance coefficient, K20, and central volume of distribution, when just using MPA plasma concentrations as observations. The second model took into consideration the EHC by including MPAG profiles as well. The results from both models showcased that the IAV played a far more significant role than the IIV in accounting for the variability of the MMF systemic appearance. This is in line with what was found in the BE study: the within-subject variability (WSV) of BE measures largely exceeded the corresponding between-subject variability. The great WSV of MMF can be mechanistically explained by the interplay of dissolution and solubility with the gastrointestinal (GI) physiological dynamics, especially the gastric emptying (GE) in the fasting state regulated by migrating motor complex, and GE and pH variations in the fed state by the caloric content with irregular patterns of GI motility and secretion. The results implied that for the immediate-release solid oral dosage forms of MMF, running a regular in vitro dissolution test for the fasting state and developing a predictive in vitro dissolution test with sufficient simulation of the GE dynamics and proximal small intestinal pH fluctuations for the fed state would be excellent surrogates for the in vivo BE test. Furthermore, a physiologically based predictive in vitro dissolution test under both fasting and fed conditions would be a new trend for the BE studies of all other HV drug products.
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Imunossupressores , Ácido Micofenólico , Simulação por Computador , Solubilidade , Equivalência TerapêuticaRESUMO
In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.
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Imunoterapia/métodos , Interleucina-8/metabolismo , Neoplasias/metabolismo , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Microambiente Tumoral , Animais , Humanos , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for regenerating a damaged heart. However, low fibroblast-cardiomyocyte conversion rates remain a major challenge in this reprogramming. To this end, here we conducted a chemical screen and identified four agents, insulin-like growth factor-1, Mll1 inhibitor MM589, transforming growth factor-ß inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed IMAP, which coordinately enhanced reprogramming efficiency. Using α-muscle heavy chain-GFP-tagged mouse embryo fibroblasts as a starting cell type, we observed that the IMAP treatment increases iCM formation 6-fold. IMAP stimulated higher cardiac troponin T and α-actinin expression and increased sarcomere formation, coinciding with up-regulated expression of many cardiac genes and down-regulated fibroblast gene expression. Furthermore, IMAP promoted higher spontaneous beating and calcium transient activities of iCMs derived from neonatal cardiac fibroblasts. Intriguingly, we also observed that the IMAP treatment repressed many genes involved in immune responses, particularly those in specific C-C chemokine signaling pathways. We therefore investigated the roles of C-C motif chemokine ligand 3 (CCL3), CCL6, and CCL17 in cardiac reprogramming and observed that they inhibited iCM formation, whereas inhibitors of C-C motif chemokine receptor 1 (CCR1), CCR4, and CCR5 had the opposite effect. These results indicated that the IMAP treatment directly suppresses specific C-C chemokine signaling pathways and thereby enhances cardiac reprogramming. In conclusion, a combination of four chemicals, named here IMAP, suppresses specific C-C chemokine signaling pathways and facilitates Mef2c/Gata4/Tbx5 (MGT)-induced cardiac reprogramming, providing a potential means for iCM formation in clinical applications.
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Reprogramação Celular/efeitos dos fármacos , Quimiocina CCL3/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Pirazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia , Tiossemicarbazonas/farmacologia , Actinina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/metabolismo , Fator de Transcrição GATA4/metabolismo , Fatores de Transcrição MEF2/metabolismo , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Receptores CCR1/metabolismo , Proteínas com Domínio T/metabolismo , Troponina T/metabolismoRESUMO
BACKGROUND: The anti-immunological rejection therapy for small-for-size syndrome (SFSS) after live donor liver transplantation (LDLT) play a central role in keeping graft survival. The hepatocyte number and grafts function has undergone real-time changes with the proliferation and apoptosis of the grafts after reperfusion. Lacking an accurate and effective treatment regiments or indicators to guide the use of immunosuppressive drugs in SFS liver transplantation has made immunotherapy after SFS liver transplantation an urgent problem to be solved. Herein, we established small-for-size (SFS) and normal size liver transplantation model in rats to explore the effective indicators in guiding immunotherapy, to find an effective way for overcoming SFSS. METHODS: Lewis rats (donors) and BN rats (recipients) were used to mimic allograft liver transplantation and treated with tacrolimus. Local graft immune response was analyzed through haematoxylin and eosin and immunohistochemistry. Flow cytometry was used to assess the overall immune status of recipient. The pharmacokinetics mechanism of immunosuppressive drugs was explored through detecting CYP3A2 expression at mRNA level and protein levels. RESULTS: The results showed the local immune reaction of SFS grafts and systemic immune responses of recipient were significantly increased compared with those in normal size grafts and their recipient at four days after liver transplantation. Regression equation was used to regulate the tacrolimus dose which not only controlled tacrolimus serum concentration effectively but alleviated liver damage and improved survival rate. CONCLUSIONS: This study showed that AST level and tacrolimus serum concentrations are effective indicators in guiding immunotherapy. Regression equation (TD = - 0.494TC-0.0035AST + 260.487) based on AST and tacrolimus serum concentration can be used as a reference for adjustment of immunotherapy after SFS liver transplantation, which is applicable in clinical practice.
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Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/imunologia , Imunossupressores/uso terapêutico , Transplante de Fígado/efeitos adversos , Tacrolimo/uso terapêutico , Animais , Aspartato Aminotransferases/sangue , Imunossupressores/sangue , Fígado/imunologia , Transplante de Fígado/métodos , Doadores Vivos , Tamanho do Órgão/imunologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Tacrolimo/sangue , Transplantes/imunologia , Resultado do TratamentoRESUMO
PURPOSE: To develop a semi-mechanistic population pharmacokinetic (PK) model to quantitate the disposition kinetics of L-histidine, a peptide-histidine transporter 1 (PHT1) substrate, in the plasma, cerebrospinal fluid and brain parenchyma of wildtype (WT) and Pht1 knockout (KO) mice. METHODS: L-[14C]Hisidine (L-His) was administrated to WT and KO mice via tail vein injection, after which plasma, cerebrospinal fluid (CSF) and brain parenchyma samples were collected. A PK model was developed using non-linear mixed effects modeling (NONMEM). The disposition of L-His between the plasma, brain, and CSF was described by a combination of PHT1-mediated uptake, CSF bulk flow and first-order micro-rate constants. RESULTS: The PK profile of L-His was best described by a four-compartment model. A more rapid uptake of L-His in brain parenchyma was observed in WT mice due to PHT1-mediated uptake, a process characterized by a Michaelis-Menten component (Vmax = 0.051 nmoL/min and Km = 34.94 µM). CONCLUSIONS: A semi-mechanistic population PK model was successfully developed, for the first time, to quantitatively characterize the disposition kinetics of L-His in brain under in vivo conditions. This model may prove a useful tool in predicting the uptake of L-His, and possibly other PHT1 peptide/mimetic substrates, for drug delivery to the brain.
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Encéfalo/efeitos dos fármacos , Histidina/química , Histidina/farmacocinética , Proteínas de Membrana Transportadoras/genética , Animais , Transporte Biológico , Barreira Hematoencefálica , Líquidos Corporais/efeitos dos fármacos , Histidina/administração & dosagem , Humanos , Cinética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Tecido Parenquimatoso/efeitos dos fármacos , Distribuição TecidualRESUMO
Terrestrialecosystems are significant carbon sinks and are crucial for understanding the regional and global carbon cycles, energy flow, and climate change. As land use change is a significant process affecting ecosystem carbon stocks and striving for land degradation neutrality (LDN), studying it is essential for comprehending the evolution of regional carbon sink functions and achieving sustainable development goals. The drastically diverse land use patterns in each of the study area's regions resulted in significant differences in carbon stock. This study explores the evolution traits of carbon stocks based on land use data and their driving mechanisms in Chongqing during the past 30 years by using spatial analysis, the InVEST model, and geographic probes. The results demonstrate that from 1990 to 2020, land degradation in Chongqing was made worse by the demand for land for construction land, but the strategy of converting cropland back to forests raised the carbon stock of forest land. The overall result is a decrease in total carbon stocks of 5.1078 Tg or 1.5%. The main pathway for carbon loss pathway in the evolution of carbon stock is the conversion of cropland to construction land, and the primary carbon compensation pathway is the conversion of grassland and cropland to forest land, with a spatial distribution characterized by "higher in the whole area and obvious local differences." The land use intensity index has the most significant influence on the evolution of carbon stock. Moreover, the interaction of pairwise factors played a more important role in affecting the evolution of carbon stocks than did each factor individually. The case study in this paper shows that land use change is a significant driving mechanism for the evolution of carbon stock, and the development of a driving model theory is appropriate for deciphering the trajectory of carbon stock evolution and offering research suggestions for other regions.
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Carbono , Ecossistema , Carbono/análise , Florestas , Sequestro de Carbono , ChinaRESUMO
On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35-59] in the D+T arm and 11% (95% CI, 3.0-25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5-NE) in the D+T arm and not estimable (95% CI, 6.6- NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6- 11.8) [HR, 0.31 (95% CI, 0.17-0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.
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Glioma , Imidazóis , Piridonas , Humanos , Criança , Piridonas/efeitos adversos , Pirimidinonas , Oximas , Glioma/tratamento farmacológico , Glioma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro, Bristol Myers Squibb Corporation) for the treatment of adult patients with locally advanced or metastatic receptor tyrosine kinase encoded by the ROS1 gene (ROS1)-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single-arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC (NCT03093116), who were either treatment naïve or had received prior ROS1 tyrosine kinase inhibitor (TKI) and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among the 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI, 68-88), median duration of response was 34.1 months (95% CI, 26-NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI, 25-52). The median duration of response was 14.8 months (95% CI, 7.6-NE); BICR-assessed responses were observed in CNS metastases in patients in both cohorts and in patients who developed resistance mutations following prior TKI therapy. The most common (>20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.
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Carcinoma Pulmonar de Células não Pequenas , Aprovação de Drogas , Neoplasias Pulmonares , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , United States Food and Drug Administration , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Estados Unidos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Idoso , Pirimidinas/uso terapêutico , Adulto , Pirazóis/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
Cropland is an essential strategic resource, for which landscape ecological security and multifunctionality evolution are related to regional stability and sustainable social development. However, few studies have explored the spatial heterogeneity of the coupling between the two from a multiregional and systematic perspective, and the interaction mechanisms have still not been thoroughly analyzed. In this study, a typical karst trough and valley area in the mountainous regions of southwest China was selected as the research object, and by establishing a multi-indicator evaluation system using a landscape pattern index, a multifunctional identification model, a coupled coordination model, and a geodetector model, the spatial variability in the evolutionary characteristics and the coupling and coordination of cropland landscape ecological security (CLES) and cropland multifunctionality (CM) in the mountainous regions of the southwest and their driving mechanisms were explored. The main results were as follows: (1) CLES in the mountainous areas of southwest China has undergone an evolutionary process of first declining and then slowly rising, with the characteristics of "fast declining in the high-value areas and slow rising in the low-value areas", while CM showed a spatial distribution of "high in the northwest and low in the northeast", with positive contributions originating from ecological functions. (2) Over the 20 years, the cropland coupling coordination degree (CCCD) values showed significant spatial heterogeneity, which was regionally expressed as ejective folds (EF) > TF (tight folds) > TLF (trough-like folds) > AF (anticlinorium folds). Low CCCD values were primarily found in the east, whereas high levels were primarily found in the west, with a rapidly diminishing trend. (3) There were differences in the driving mechanisms of CCDD in different landscapes, but GDP was still the determining factor and had a limiting effect. Hence, we call for the adoption of a "function over pattern" approach in areas with more development constraints and a "pattern over function" approach in areas with fewer development constraints. Ultimately, this study will contribute to the formation of a coupled cropland mechanism system described as the "multi-mechanisms drive, multi-elements integrated" system. In conclusion, this study can provide a better understanding of the relationship between cropland patterns and multifunctionality, which can help provide a basis for cropland conservation and landscape planning in similar mountainous areas and promote the achievement of sustainable agricultural development goals in the mountainous areas of southwest China.
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Agricultura , Conservação dos Recursos Naturais , Conservação dos Recursos Naturais/métodos , Desenvolvimento Sustentável , China , Produtos Agrícolas , EcossistemaRESUMO
Revealing the general laws of land use transformation (LUT) under the coupling evolution of different socio-economic and eco-environment (SE-EE) in mountainous areas is of great significance for rational use of land resources, regional socio-economic development, and eco-environment protection. This paper constructs a research framework of LUT under the coupling evolution of SE-EE and takes Fengjie County as an example to conduct a case study. The results show (1) the socio-economic development level and eco-environment quality showed an overall growth trend from 2000 to 2020, showed the distribution pattern of high in the Yangtze River valley and low in the mountainous areas, and low in the Yangtze River valley and high in the mountainous areas respectively. (2) The coupling evolution of SE-EE showed five types: synchronous development of SE-EE, socio-economic development and ecological retarded, socio-economic retarded and ecological restoration, low socio-economic development level, and low eco-environment quality. (3) The transformation of land use quantity, structure, and function corresponded to the coupling evolution of SE-EE. Cultivated land was reduced when the socio-economic development level was relatively high, and the function changed from production to ecological and eco-economic. When the eco-environment quality was high, cultivated land was reduced, and the function changed from production to ecological. (4) The framework constructed in this paper is universal to the mountainous areas represented by the Three Gorges Reservoir Area (TGRA) and the plain areas where the LUT and SE-EE evolution are different from the mountainous areas.
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Conservação dos Recursos Naturais , Desenvolvimento Econômico , Conservação dos Recursos Naturais/métodos , China , Rios , Fatores Socioeconômicos , EcossistemaRESUMO
On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose. Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% confidence interval: 27-45). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Hiperfosfatemia , Adulto , Humanos , Estados Unidos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/patologia , Aprovação de Drogas , United States Food and Drug Administration , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. The primary endpoint was overall response rate (ORR) by RECIST 1.1 as per blinded central review committee (BIRC) assessment. The main secondary endpoint was duration of response (DOR) per BIRC assessment. Eighty-four eligible patients received the combination tucatinib and trastuzumab. With a median follow-up of 16 months, the ORR was 38% [95% confidence interval (CI): 28-49] and median DOR was 12.4 months (95% CI: 8.5-20.5); 81% of responders had a response lasting more than 6 months. The most common adverse reactions observed in at least 20% of patients receiving tucatinib in combination with trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and fever. FDA concluded that the magnitude of ORR and durable responses observed in patients treated with tucatinib in combination with trastuzumab in the MOUNTAINEER trial are clinically meaningful, particularly in the context of a disease with estimated survival of 6-7 months with available therapy. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of the data supporting this accelerated approval.
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Neoplasias da Mama , Neoplasias Colorretais , Humanos , Feminino , Trastuzumab , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Quinazolinas , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológicoRESUMO
The FDA granted accelerated approval for amivantamab-vmjw (hereafter referred to as amivantamab), a bispecific antibody directed against EGFR and mesenchymal-epithelial transition receptor, on May 21, 2021, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Approval was based on results of an ongoing, multicenter, nonrandomized, open-label, multicohort clinical trial (CHRYSALIS, NCT02609776), demonstrating a substantial overall response rate (ORR) and durable responses, with an ORR of 40% [95% confidence interval (CI): 29-51] and a median response duration of 11.1 months (95% CI: 6.9-not evaluable). Guardant360 CDx was contemporaneously approved as a companion diagnostic for this indication to identify EGFR exon 20 insertion mutations in plasma specimens. The most notable safety finding was the high incidence (66%) of infusion-related reactions, which is addressed in both the Dosage and Administration and Warnings and Precautions sections of the product label. Other common adverse reactions (occurring in ≥20% of patients) were rash, paronychia, musculoskeletal pain, dyspnea, nausea and vomiting, fatigue, edema, stomatitis, cough, and constipation. The approval of amivantamab was the first approval of a targeted therapy for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutagênese Insercional , Receptores ErbB/genética , Éxons , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
On September 21, 2022, the FDA granted accelerated approval to selpercatinib (Retevmo, Eli Lilly and Company) for the treatment of adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The approval was based on data from Study LOXO-RET-17001 (LIBRETTO-001; NCT03157128), an international, non-randomized, multi-cohort clinical trial that included patients with advanced solid tumors harboring RET alterations. The overall response rate in 41 patients with locally advanced or metastatic RET fusion-positive solid tumors other than non-small cell lung cancer (NSCLC) or thyroid cancer was 44% [95% confidence interval (CI), 28%-60%], with median duration of response 24.5 months (95% CI, 9.2-not evaluable). Patients with 10 of 14 tumor types with a variety of fusion partners had objective responses, including patients with the following tumors: pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft-tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma. The recommendation for approval was supported by results from LIBRETTO-001 in patients with RET fusion-positive NSCLC and thyroid cancer, which formed the basis of prior approvals in these tumor types. The most common adverse reactions (>25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. This is the first tissue-agnostic approval of a RET-directed targeted therapy.
Assuntos
Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias Pancreáticas , Neoplasias da Glândula Tireoide , Adulto , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Proteínas Proto-Oncogênicas c-ret/genéticaRESUMO
Although siRNA techniques have been broadly applied as a tool for gene knockdown, substantial challenges remain in achieving efficient delivery and in vivo efficacy. In particular, the low efficiency of target gene silencing in vivo is a critical limiting step to the clinical application of siRNA therapies. Poly(amidoamine) (PAMAM) dendrimers are widely used as carriers for drug and gene delivery; however, in vivo siRNA delivery by PAMAM dendrimers remains to be carefully investigated. In this study, the effectiveness of G5 and G6 PAMAM dendrimers with 8% of their surface amines conjugated to MPEG-5000 was studied for siRNA delivery in vitro and for intramuscular in vivo delivery in mice. The results from the PEG-modified dendrimers were compared to the results from the parent dendrimers as well as Lipofectamine 2000 and INTERFERin. Both PEG-modifed dendrimers protect the siRNA from being digested by RNase and gave high transfection efficiency for FITC-labeled siRNA in the primary vascular smooth muscle cells (VSMC) and mouse peritoneal macrophages. The PEG-modified dendrimers achieved knockdown of both plasmid (293A cells) and adenovirus-mediated green fluorescence protein (GFP) expression (Cos7 cells) in vitro with efficiency similar to that shown for Lipofectamine 2000. We further demonstrated in vivo that intramuscular delivery of GFP-siRNA using PEG-modified dendrimer significantly suppressed GFP expression in both transiently adenovirus infected C57BL/6 mice and GFP transgenic mice.
Assuntos
Dendrímeros/química , Inativação Gênica/fisiologia , Polietilenoglicóis/química , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Animais , Animais Recém-Nascidos , Células COS , Linhagem Celular , Cricetinae , Feminino , Fluoresceína-5-Isotiocianato/química , Proteínas de Fluorescência Verde/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , RNA Interferente Pequeno/químicaRESUMO
A rare disease is defined as a condition affecting fewer than 200 000 people in the United States by the Orphan Drug Act. For rare diseases, it is challenging to enroll a large number of patients and obtain all critical information to support drug approval through traditional clinical trial approaches. In addition, over half of the population affected by rare diseases are children, which presents additional drug development challenges. Thus, maximizing the use of all available data is in the interest of drug developers and regulators in rare diseases. This brings opportunities for model-informed drug development to use and integrate all available sources and knowledge to quantitatively assess the benefit/risk of a new product under development and to inform dosing. This review article provides an overview of 4 broad categories of use of model-informed drug development in drug development and regulatory decision making in rare diseases: optimizing dose regimen, supporting pediatric extrapolation, informing clinical trial design, and providing confirmatory evidence for effectiveness. The totality of evidence based on population pharmacokinetic simulation as well as exposure-response relationships for efficacy and safety, provides the regulatory ground for the approval of an unstudied dosing regimen in rare diseases without the need for additional clinical data. Given the practical and ethical challenges in drug development in rare diseases, model-informed approaches using all collective information (eg, disease, drug, placebo effect, exposure-response in nonclinical and clinical settings) are powerful and can be applied throughout the drug development stages to facilitate decision making.
Assuntos
Desenvolvimento de Medicamentos , Doenças Raras , Humanos , Criança , Doenças Raras/tratamento farmacológico , Aprovação de Drogas , Simulação por ComputadorRESUMO
The FDA approved capmatinib and tepotinib on May 6, 2020, and February 3, 2021, respectively. Capmatinib is indicated for patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors have a mutation leading to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. Tepotinib is indicated for mNSCLC harboring MET exon 14 skipping alterations. The approvals were based on trials GEOMETRY mono-1 (capmatinib) and VISION (tepotinib). In GEOMETRY mono-1, overall response rate (ORR) per Blinded Independent Review Committee (BIRC) was 68% [95% confidence interval (CI), 48-84] with median duration of response (DoR) 12.6 months (95% CI, 5.5-25.3) in 28 treatment-naïve patients and 41% (95% CI: 29, 53) with median DoR 9.7 months (95% CI, 5.5-13) in 69 previously treated patients with NSCLC with mutations leading to MET exon 14 skipping. In VISION, ORR per BIRC was 43% (95% CI: 32, 56) with median DoR 10.8 months (95% CI, 6.9-not estimable) in 69 treatment-naïve patients and 43% (95% CI, 33-55) with median DoR 11.1 months (95% CI, 9.5-18.5) in 83 previously-treated patients with NSCLC harboring MET exon 14 alterations. These are the first two therapies to be FDA approved specifically for patients with metastatic NSCLC with MET exon 14 skipping.