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Expert Opin Drug Metab Toxicol ; 14(9): 929-936, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30099912


INTRODUCTION: Biomarkers are one of the drug development tools that are being developed through collaborative efforts among multiple stakeholder communities to enhance the drug development process. Biomarkers of acute drug-induced renal injury as used in drug development are more commonly referred to as renal safety biomarkers, the focus of this manuscript. Areas covered: This manuscript provides an overview of the history and evolution of the United States Food and Drug Administration's Center for Drug Evaluation and Research's Biomarker Qualification Program. In addition, a regulatory perspective on the potential for renal safety biomarkers to accelerate medical and pharmaceutical research is presented. The first qualification submissions (acute kidney injury biomarkers) are discussed, including how the FDA review process affected the evolution of the biomarker qualification process and the future of biomarker discovery, development, and use. This manuscript also discusses a new repository for data on novel translational safety biomarkers from drug development programs. Expert opinion: In addition to the qualification of novel biomarkers, a key achievement of the first submission for qualification was the bringing together of multiple stakeholder communities to optimize the process. Early qualification reviews provided valuable lessons that informed an overarching approach of how to develop a biomarker for regulatory use.

Lesão Renal Aguda/induzido quimicamente , Biomarcadores/metabolismo , Desenho de Drogas , Lesão Renal Aguda/diagnóstico , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Estados Unidos , United States Food and Drug Administration
J Am Soc Nephrol ; 26(12): 2930-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26078365


Absent a remission of proteinuria, primary membranous nephropathy (MN) can lead to ESRD over many years. Therefore, use of an earlier end point could facilitate the conduct of clinical trials. This manuscript evaluates complete remission (CR) and partial remission (PR) of proteinuria as surrogate end points for a treatment effect on ESRD in patients with primary MN with heavy proteinuria. CR is associated with a low relapse rate and excellent long-term renal survival, and it plausibly reflects remission of the disease process that leads to ESRD. Patients who achieve PR have better renal outcomes than those who do not but may have elevated relapse rates. How long PR must be maintained to yield a benefit on renal outcomes is also unknown. Hence, available data suggest that CR could be used as a surrogate end point in primary MN, whereas PR seems reasonably likely to predict clinical benefit. In the United States, surrogate end points that are reasonably likely to predict clinical benefit can be used as a basis for accelerated approval; treatments approved under this program must verify the clinical benefit in postmarketing trials. Additional analyses of the relationship between treatment effects on CR and PR and subsequent renal outcomes would inform the design of future clinical trials in primary MN.

Biomarcadores/urina , Determinação de Ponto Final , Glomerulonefrite Membranosa/tratamento farmacológico , Falência Renal Crônica/prevenção & controle , Proteinúria/urina , Animais , Progressão da Doença , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Falência Renal Crônica/etiologia , Proteinúria/etiologia , Recidiva , Indução de Remissão , Resultado do Tratamento
Nat Biotechnol ; 28(5): 455-62, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20458315


The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

Biomarcadores Farmacológicos , Aprovação de Drogas/legislação & jurisprudência , Rim , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Europa (Continente) , Humanos , Rim/efeitos dos fármacos , Rim/lesões , Preparações Farmacêuticas/normas , Estados Unidos , United States Food and Drug Administration
Acta Biomater ; 6(4): 1529-35, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19837194


Brushite (CaHPO(4) x 2H(2)O)-forming calcium phosphate cements are of great interest as bone replacement materials because they are resorbable in physiological conditions. However, their short setting times and low mechanical strengths limit broad clinical application. In this study, we showed that a significant improvement of these properties of brushite cement could be achieved by the use of magnesium-substituted beta-tricalcium phosphate with the general formula Mg(x)Ca((3-x))((PO(4))(2) with 0 < x < 3 as cement reactants. The incorporation of magnesium ions increased the setting times of cements from 2 min for a magnesium-free matrix to 8-11 min for Mg(2.25)Ca(0.75)(PO(4))(2) as reactant. At the same time, the compressive strength of set cements was doubled from 19 MPa to more than 40 MPa after 24h wet storage. Magnesium ions were not only retarding the setting reaction to brushite but were also forming newberyite (MgHPO(4) x 3H(2)O) as a second setting product. The biocompatibility of the material was investigated in vitro using the osteoblast-like cell line MC3T3-E1. A considerable increase of cell proliferation and expression of alkaline phosphatase, indicating an osteoblastic differentiation, could be noticed. Scanning electron microscopy analysis revealed an obvious cell growth on the surface of the scaffolds. Analysis of the culture medium showed minor alterations of pH value within the physiological range. The concentrations of free calcium, magnesium and phosphate ions were altered markedly due to the chemical solubility of the scaffolds. We conclude that the calcium magnesium phosphate (newberyite) cements have a promising potential for their use as bone replacement material since they provide a suitable biocompatibility, an extended workability and improved mechanical performance compared with brushite cements.

Materiais Biocompatíveis/farmacologia , Cimentos para Ossos/farmacologia , Teste de Materiais , Fenômenos Mecânicos/efeitos dos fármacos , Transição de Fase/efeitos dos fármacos , Fosfatos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Força Compressiva/efeitos dos fármacos , Meios de Cultura/química , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/ultraestrutura , Tamanho da Partícula , Fatores de Tempo , Difração de Raios X