Drug safety testing paradigm, current progress and future challenges: an overview

Abstract

Early assessment of the toxicity potential of new molecules in pharmaceutical industry is a multi-dimensional task involving predictive systems and screening approaches to aid in the optimization of lead compounds prior to their entry into development phase. Due to the high attrition rate in the pharma industry in last few years, it has become imperative for the nonclinical toxicologist to focus on novel approaches which could be helpful for early screening of drug candidates. The need is that the toxicologists should change their classical approach to a more investigative approach. This review discusses the developments that allow toxicologists to anticipate safety problems and plan ways to address them earlier than ever before. This includes progress in the field of in vitro models, surrogate models, molecular toxicology, 'omics' technologies, translational safety biomarkers, stem-cell based assays and preclinical imaging. The traditional boundaries between teams focusing on efficacy/ safety and preclinical/ clinical aspects in the pharma industry are disappearing, and translational research-centric organizations with a focused vision of bringing drugs forward safely and rapidly are emerging. Today's toxicologist should collaborate with medicinal chemists, pharmacologists, and clinicians and these value-adding contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.

An Overall Comparison of Small Molecules and Large Biologics in ADME Testing

“…As highlighted in Table 1, due to the nature of various characteristics between SMs and LMs, the focus on ADME studies of LMs is thus different from SMs in particular for drug metabolite safety testing and DDI evaluations. In these aspects, in vitro models and in vivo studies and related bioanalysis including transporter studies and safety evaluation and high-throughput screening approaches for SMs have well been established across pharmaceutical industry [12][13][14][15][16][17][18][19][20]. Typical in vitro ADME tests for SMs are metabolic stability by liver microsmoes or/and hepatocytes and passive permeability on cell-line models based on Caco-2 or MDCK assays, which are commonly utilized to predict in vivo clearance and absorption or bioavailability as well as potential drug-drug interaction (DDI) evaluations and metabolism pathway studies.…”

Propuesta para seleccionar aceites esenciales de plantas de Colombia para investigación con base en su citotoxicidad

“…La experimentación animal se recomienda ya que permite inferir con cierta confiabilidad el grado de afectación sobre diversos órganos humanos en el humano, en especial hígado, riñón y cerebro (12), aunque tiene tres limitaciones mayores: i) alto costo en infraestructura para cumplir con parámetros de buenas prácticas; ii) bajo rendimiento debido a que un limitado número de muestras se puede analizar en corto tiempo; iii) el análisis está restringido a muestras que no causen dolor intenso o sufrimiento permanente al animal según normas éticas actuales (12,13). Por estas dificultades viene aummentado el uso de ensayos basados en célula (citotoxicidad in vitro) y el interés de la comunidad científica para que los resultados se tengan en cuenta en la regulación de productos recién descubiertos (14). Citotoxicidad se define como el efecto acumulativo sobre el número de células debido a apoptosis, necrosis o reducción de la tasa de replicación celular.…”

Assessment of food toxicology

“…Cell-specific biomarkers on gene, protein or metabolite levels can be measured by toxicogenomics, toxicoproteonomics or toxicometabonomics, respectively [6,27,[35][36][37][38][39][40]. The integration of food toxicology data obtained via in vitro biochemical, cell-based, in vivo animal models and in silico systems have led to a mechanistic knowledge of systemic or organ-specific toxicity in humans and the identification and use of specific surrogate biomarkers in clinical settings.…”

“…The deeper understanding of the molecular mode of action on key targets of biological pathways have enhanced the predictivity and robustness of in vitro cell-based toxicity models and thus led to the improvement of food safety. Moreover, although in early development, stem cell-based screening or three-dimensional organotypic models will further increase the predictivity of acute toxicity and help to answer fundamental biological questions and/or enable testing of novel therapeutic approaches [6,7,[53][54][55][56][57].…”

“…M a n u s c r i p t determined in animal models to a mechanism-based approach by in silico methods [6,7,29,33,34].…”