Applications of Model-Based Target Pharmacology Assessment in Defining Drug Design and DMPK Strategies: GSK Experiences.

Many critical decisions faced in early discovery require a thorough understanding of the dynamic behavior of pharmacological pathways following target engagement. From fundamental decisions on the optimal target to pursue and the ultimate drug product profile (combination of modality, potency, and compound properties) expected to elicit the desired clinical outcome to tactical program decisions such as what chemical series to pursue, what chemical properties require optimization, and what compounds to synthesize and progress, all demand detailed consideration of pharmacodynamics. Model-based target pharmacology assessment (mTPA) is a computational approach centered around large-scale virtual exploration of pharmacokinetic and pharmacodynamic models built early in discovery to guide these decisions. The present work summarizes several examples (use cases) from programs at GlaxoSmithKline that demonstrate the utility of mTPA throughout the drug discovery lifecycle.

Small-Molecule Lead-Finding Trends across the Roche and Genentech Research Organizations.

The origin of small-molecule leads that were pursued across the independent research organizations Roche and Genentech from 2009 to 2020 is described. The identified chemical series are derived from a variety of lead-finding methods, which include public information, high-throughput screening (both full file and focused), fragment-based design, DNA-encoded library technology, use of legacy internal data, in-licensing, and de novo design (often structure-based). The translation of the lead series into in vivo tool compounds and development candidates is discussed as are the associated biological target classes and corresponding therapeutic areas. These analyses identify important trends regarding the various lead-finding approaches, which will likely impact their future application in the Roche and Genentech research groups. They also highlight commonalities and differences across the two independent research organizations. Several caveats associated with the employed data collection and analysis methodologies are included to enhance the interpretation of the presented information.

Superación profesional sobre uso racional de medicamentos dirigida a los médicos generales integrales / Professional improvement on the rational use of medications intended comprehensive general practitioners

RESUMEN Fundamento: el vertiginoso avance de la industria farmacéutica exige al médico general integral un proceso de superación continuo que favorezca el uso racional de los medicamentos. Objetivo: caracterizar la superación de estos profesionales relacionada con el uso racional de medicamentos en la Facultad de Medicina 1 de Santiago de Cuba. Métodos: se realizó un estudio descriptivo transversal en el que se analizaron las actividades de superación profesional de cinco cursos académicos desde el 2014 al 2019 a través de la revisión documental de los planes de superación profesional, así como los programas correspondientes. Resultados: las actividades relacionadas con el uso racional de medicamentos eran insuficientes y con tendencia a la disminución de un curso a otro; la forma de organización del posgrado más empleada fueron los cursos, seguidas de los talleres. Para incorporar los contenidos de uso racional de medicamentos se utilizaron, con más frecuencia, elementos de terapéutica de una enfermedad o grupo de estas así como la introducción de la medicina natural y tradicional. En las actividades se abordaron aspectos novedosos, pero no se hizo referencia a la terapéutica razonada. Conclusiones: se caracterizó la superación profesional para los médicos generales integrales relacionada con el uso racional de medicamentos la cual fue valorada como insuficiente por lo que urge retomar los aspectos que resultaron deficitarios en esta caracterización.

ABSTRACT Background: the vertiginous advance of the pharmaceutical industry demands from the comprehensive general practitioner a continuous improvement process that favors the rational use of medications. Objective: to characterize the improvement of these professionals related to the rational use of medications in the Faculty of Medicine 1 of Santiago de Cuba. Methods: a cross-sectional descriptive study was carried out in which the professional improvement activities of five academic courses from 2014 to 2019 were analyzed through the documentary review of the professional improvement plans, as well as the corresponding programs. Results: the activities related to the rational use of medications were insufficient and tended to decrease from one course to another; the most used form of postgraduate organization were courses, followed by workshops. To incorporate the contents of rational use of medications, therapeutic elements of a disease or group of diseases were used, as well as the introduction of Herbal and Folk medicine. In the activities, novel aspects were addressed, but no reference was made to reasoned therapy. Conclusions: professional improvement for comprehensive general practitioners related to the rational use of medications was characterized, which was assessed as insufficient, so it is urgent to retake the aspects that were deficient in this characterization.

Residuos farmacéuticos domiciliarios en el medio ambiente: de la preocupación a la acción

[Extracto]. Al editor: Los autores queremos hacer un llamado de atención a la comunidad sobre un tema de salud pública que silenciosamente afecta a todos los seres vivos. Se trata de la presencia de contaminantes emergentes (CE) (ej. plaguicidas, cosméticos, nanomateriales, fármacos, entre otros) en el medioambiente. Los CE se caracterizan por su persistencia, bioconcentración, bioacumulación, biomagnificación, y movilidad ambiental. Los efectos de los CE sobre la salud humana y otros seres vivos es motivo de estudio desde hace poco tiempo, por ello en latinoamérica mayormente no se dispone de normativa legal que regule este tema. En países como, Brasil, Canadá, España, Francia, Inglaterra, Portugal y Uruguay se han realizado investigaciones que determinan la presencia de algunos CE en la entrada y salida de las plantas depuradoras de aguas servidas, demostrándose que no es posible su completa eliminación. El problema radica en que se desconoce su toxicidad y la de sus metabolitos, que en ocasiones es mayor. Entre los CE detectados en estos estudios, destacan los siguientes fármacos: carbamazepina, atenolol, sulfadiazina, paracetamol, eritromicina, ácido salicílico, diclofenaco, ibuprofeno, 17 β-estradiol, progesterona y levonorgestrel.

The future of biomolecular simulation in the pharmaceutical industry: what we can learn from aerodynamics modelling and weather prediction. Part 1. understanding the physical and computational complexity of in silico drug design.

The predictive power of simulation has become embedded in the infrastructure of modern economies. Computer-aided design is ubiquitous throughout industry. In aeronautical engineering, built infrastructure and materials manufacturing, simulations are routinely used to compute the performance of potential designs before construction. The ability to predict the behaviour of products is a driver of innovation by reducing the cost barrier to new designs, but also because radically novel ideas can be piloted with relatively little risk. Accurate weather forecasting is essential to guide domestic and military flight paths, and therefore the underpinning simulations are critical enough to have implications for national security. However, in the pharmaceutical and biotechnological industries, the application of computer simulations remains limited by the capabilities of the technology with respect to the complexity of molecular biology and human physiology. Over the last 30 years, molecular-modelling tools have gradually gained a degree of acceptance in the pharmaceutical industry. Drug discovery has begun to benefit from physics-based simulations. While such simulations have great potential for improved molecular design, much scepticism remains about their value. The motivations for such reservations in industry and areas where simulations show promise for efficiency gains in preclinical research are discussed. In this, the first of two complementary papers, the scientific and technical progress that needs to be made to improve the predictive power of biomolecular simulations, and how this might be achieved, is firstly discussed (Part 1). In Part 2, the status of computer simulations in pharma is contrasted with aerodynamics modelling and weather forecasting, and comments are made on the cultural changes needed for equivalent computational technologies to become integrated into life-science industries.

Toward Interprofessional Education of Pharmacogenomics: An Interdisciplinary Assessment.

INTRODUCTION: Pharmacogenomics, which emerged from disciplines such as pharmacology and genetics, is an increasingly important interdisciplinary field of health research, as indicated by the rapid growth of related literature. The aim of this study was to evaluate knowledge among genetics and pharmacology health-care students and to evaluate their exposure to and perceptions of pharmacogenomics. METHODS: An anonymous, 28-item online survey was distributed to medical and pharmacy students enrolled at Yarmouk University, Jordan. RESULTS: The respondents (n = 300) had an overall moderate level of knowledge regarding genetics and pharmacology. Most respondents recognized the benefits of pharmacogenomics for therapy optimization, but they had insufficient exposure to the topic. Most respondents supported providing pharmacogenetic testing in Jordan. The most preferred educational format in pharmacogenomics was integration in pharmacology courses. DISCUSSION/CONCLUSION: Medical and pharmacy students are becoming increasingly aware of the importance of pharmacogenomics in therapy optimization. Challenges such as the complexity of the topic and low retention of previous knowledge should be addressed to promote pharmacogenomics education. More work is needed to increase students' exposure to pharmacogenomics information. A deeper integration of pharmacogenomics applications into pharmacology courses is proposed to emphasize applications of pharmacogenomics.

Revisão e sistematização de rotinas em uma central de preparo de medicamentos antineoplásicos / Review and systematization of routines in an antineoplastic drug preparation center

A indústria farmacêutica é amplamente regulada e emprega diversas estratégias para alcançar a qualidade necessária. As normas ISO constituem importante ferramenta neste objetivo e consideram que a necessidade de padronização de um processo deverá impor às empresas a documentação do processo. Cada empresa terá uma organização e uma necessidade de documentação diferente, que, de modo geral, se organizará em 4 níveis hierárquicos de documentos: manual da qualidade, procedimentos, instruções de trabalho e formulários de registro. Cada tipo de documento tem suas próprias características e exigências, que são definidas pela norma. As empresas deverão decidir quais processos documentar e a maneira como essa documentação será realizada, evitando engessamento e burocratização do trabalho, com custos de tempo, pessoal e financeiro, mas garantindo a padronização necessária para atingir níveis ótimos de qualidade. Objetivos: Este trabalho objetiva elaborar e/ou revisar conjunto de Procedimentos Operacionais e Instruções de Trabalho que visem a Garantia da Qualidade das Preparações Antineoplásicas na Central de Misturas Intravenosas do HNSC, conforme normas e resoluções técnicas aplicáveis, cobrindo o fluxo do medicamento de seu recebimento na CMI até à dispensação ao paciente. Justificativa e referencial teórico: Desde a publicação do relatório "To err is human" a segurança do paciente tornou-se preocupação recorrente nos estabelecimentos de saúde de todo mundo. A OMS e outras instituições propuseram indicadores e metas para melhoria da segurança do paciente, no Brasil tais metas foram incorporadas ao Plano Nacional de Segurança do Paciente publicado pelo Ministério da Saúde, apresentando diretrizes norteadoras para elaboração de estratégias, políticas, ações e normatizações no âmbito...(AU)

Type-I heavy tailed family with applications in medicine, engineering and insurance.

In the present study, a new class of heavy tailed distributions using the T-X family approach is introduced. The proposed family is called type-I heavy tailed family. A special model of the proposed class, named Type-I Heavy Tailed Weibull (TI-HTW) model is studied in detail. We adopt the approach of maximum likelihood estimation for estimating its parameters, and assess the maximum likelihood performance based on biases and mean squared errors via a Monte Carlo simulation framework. Actuarial quantities such as value at risk and tail value at risk are derived. A simulation study for these actuarial measures is conducted, proving that the proposed TI-HTW is a heavy-tailed model. Finally, we provide a comparative study to illustrate the proposed method by analyzing three real data sets from different disciplines such as reliability engineering, bio-medical and financial sciences. The analytical results of the new TI-HTW model are compared with the Weibull and some other non-nested distributions. The Baysesian analysis is discussed to measure the model complexity based on the deviance information criterion.

QSP-IO: A Quantitative Systems Pharmacology Toolbox for Mechanistic Multiscale Modeling for Immuno-Oncology Applications.

Immunotherapy has shown great potential in the treatment of cancer; however, only a fraction of patients respond to treatment, and many experience autoimmune-related side effects. The pharmaceutical industry has relied on mathematical models to study the behavior of candidate drugs and more recently, complex, whole-body, quantitative systems pharmacology (QSP) models have become increasingly popular for discovery and development. QSP modeling has the potential to discover novel predictive biomarkers as well as test the efficacy of treatment plans and combination therapies through virtual clinical trials. In this work, we present a QSP modeling platform for immuno-oncology (IO) that incorporates detailed mechanisms for important immune interactions. This modular platform allows for the construction of QSP models of IO with varying degrees of complexity based on the research questions. Finally, we demonstrate the use of the platform through two example applications of immune checkpoint therapy.

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation.

INTRODUCTION: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP). METHODS: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays. RESULTS: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology. The most frequently observed drug-mediated effects included an increased heart rate, increased arterial blood pressure, hERG (IKr) block, decreased arterial blood pressure, decreased heart rate, QTc prolongation, and changes in body temperature. Broadly implemented study practices included Latin square crossover study design with n = 4 for nonrodent CV studies, statistical analysis of data (eg, analysis of variance), use of arrhythmia detection software, and the inclusion of data from all study animals when integrating SP studies into toxicology studies. Most responders frequently used individual animal housing conditions. Responders commonly evaluated drug effects on multiple ion channels, but in silico modeling methods were used much less frequently. Most responders rarely measured the J-Tpeak interval in CV studies. Uncertainties relative to Standard for Exchange of Nonclinical Data applications for data derived from CV SP studies were common. Although available, the use of human induced pluripotent stem cell cardiomyocytes remains rare. The respiratory SP study was rarely involved with identifying drug-induced functional issues. Responders indicated that the study-derived no observed effect level was more frequently determined than the no observed adverse effect level in CV SP studies; however, a large proportion of survey responders used neither.

Lower scores in pharmacokinetics than in pharmacodynamics assessment among students in a health and life sciences curriculum.

In pharmacology teaching, pharmacokinetics (PK) and pharmacodynamics (PD) may be defined as part of the 'general pharmacology' domain, whereas effects of drugs on the autonomic nervous system and clinical trial design might be defined as part of the 'medical' and 'clinical' pharmacology domain, respectively. We recently designed a pharmacology course covering these domains for second year Health and Life Sciences students at the Vrije Universiteit Amsterdam (VU). We used a combination of lectures, problem-based learning and practicals to transfer knowledge to students in order for them to acquire sufficient knowledge and insight to solve real-world pharmacological problems. To evaluate whether we 1) successfully aligned our course objectives with both our teaching strategy and assessment, and 2) to identify topics in our course that would benefit from improvement in teaching strategy and/or effort, we determined success rate of the exam questions in above-defined pharmacology domains. We analyzed 3 consecutive second year cohorts (n = 377) of students enrolled in our course, and found a statistically significant reduction in success rate in exam questions of the general pharmacology domain (especially in PK), compared to domains covering 'medical' and 'clinical' pharmacology. In addition, we found lower success rates for 'knows how' questions compared to 'knows' questions in the combined PK/PD domain. Our data show that we overall succeeded in aligning our course objectives with both our teaching strategy and assessment, but that outcomes on the PK domain might benefit from additional attention.

Development of a safe drug administration assessment instrument for nursing students.

OBJECTIVE: to determine the content and face validity of a safe drug administration assessment instrument for nursing students. METHOD: quantitative, descriptive study. The literature on medication errors made by students was analyzed, and an instrument was developed using the Architecture of Integrated Information Systems and the Work Breakdown Structure. Face validity was analyzed using the nominal technique, with experts in education, management, research and/or clinical practice. RESULTS: nine experts participated in the validation process, which resulted in an instrument containing 8 sub-processes and 58 items, adjusted to the simulation environment and to clinical practice. CONCLUSION: the instrument may be used for the evaluation of safe drug administration by nursing students, especially in a simulation environment.