Changing Requirements for Evaluation of Pharmacologic Agents

PEDIATRICS ◽  
2004 ◽  
Vol 113 (Supplement_3) ◽  
pp. 1128-1132
Author(s):  
Russell W. Chesney ◽  
Michael L. Christensen
Keyword(s):  
Drug Development ◽  
Drug Administration ◽  
Drug Testing ◽  
Age Groups ◽  
New Drugs ◽  
Lack Of Information ◽  
Vulnerable Patients ◽  
Therapeutic Research ◽  
Effective Use ◽  
Pharmacologic Agents

Children sadly have been excluded from some of the therapeutic advances that have marked pharmaceutical drug development during the past 100 years. Most drugs in use today lack Food and Drug Administration approval for use in children or are restricted to certain pediatric age groups, predominately older than 12 years. Only a few of the new drugs approved each year have pediatric indications and dosing guidelines described in the drug labeling information. However, many of these drugs are used in children. The lack of suitable information places children at risk for over- or underdosing, and there is a lack of suitable dosage forms, which can result in improper drug administration. This lack of information on the safe and effective use of drugs in the most vulnerable patients—infants and neonates—is of greatest concern. Recent changes in the regulations that govern drug development has dramatically increased the number of drugs that undergo testing in children. This article reviews new laws that govern drug testing in children and the use of children in therapeutic research.

Drug administration

2010 ◽  
Author(s):  
Carol Barron ◽  
Eleanor Hollywood
Keyword(s):  
Young People ◽  
Drug Development ◽  
Drug Administration ◽  
Age Groups ◽  
Healthcare Services ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Children And Young People ◽  
Child Population ◽  
Commercial Market ◽  
Routes Of Drug Administration

By the end of this chapter you will be introduced to the concepts of pharmacokinetics and pharmacodynamics with specific emphasis on the infant, child, and young person. You will be presented with the current evidenced- based practice in relation to differing routes of drug administration in children and young people, underpinned by a firm rationale throughout. The key points to consider when administering medications via differing routes to children will be explored. Throughout this chapter the importance and method of drug calculations and mental mathematics will be highlighted, as befits their importance in the safe preparation and administration of all medications. It is anticipated that you will be able to do the following once you have read and studied this chapter: ● Discuss pharmacokinetics and pharmacodynamics as they relate to drug administration with children. ● Understand the mathematical calculations required to accurately prepare and administer medications in children. ● Understand the key nursing skills required to administer medications to children and young people via differing routes. Historically, drug development specifically for children was only conducted for common disorders/diseases where medication was part of the accepted treatment. Examples are medicines for epilepsy or asthma, antibiotics, or vaccines (Rose, 2005). Because the numbers of children are small in comparison with adults, and the child population is subdivided into age groups from neonates to teenagers, pharmaceutical companies are governed by the commercial market. Consequently they assign limited resources to drug development in the child population because of more limited profit margins. However, this situation is changing, as the European Union established a European Network for Drug Investigation in Children in 1998, with a commitment to improve both clinical use and research into drugs for children (Van den Anker & Choonara, 1999). An international meta-register of controlled clinical trials has been created where particular emphasis is placed on paediatric aspects (Bonati et al., 2001). All of these initiatives serve to change the prevailing view of children as ‘therapeutic orphans’ to an acknowledgement that children are consumers of healthcare services and as such have the right both ethically and morally to medications that are designed and trialled for them specifically.

Insights into newly approved drugs from a medicinal chemistry perspective

2021 ◽  
Vol 21 ◽  
Author(s):  
Elys Juliane Cardoso Lima ◽  
Renan Augusto Gomes ◽  
Evelin Fornari ◽  
Flavio da Silva Emery ◽  
Gustavo Henrique Goulart Trossini
Keyword(s):  
Drug Design ◽  
Drug Development ◽  
Drug Administration ◽  
Medicinal Chemistry ◽  
Food And Drug Administration ◽  
New Drugs ◽  
Design And Optimization ◽  
Continuous Evolution ◽  
Development Pipeline ◽  
Approved Drugs

: The development of new drugs is becoming notably harder each decade. To overcome the present pitfalls in the drug development pipeline, such as those related to potency, selectivity, or absorption, distribution, metabolism, excretion and toxicity properties, medicinal chemistry strategies need to be in continuous evolution and need to become even more multidisciplinary. In this review, we present how structure-based, ligand-based, and fragment-based drug design (SBDD, LBDD, and FBDD, respectively) and their respective techniques were used for the design and optimization of successful cases of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA).

scholarly journals Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2420-2428 ◽  
Author(s):  
Roland B. Walter ◽  
Frederick R. Appelbaum ◽  
Martin S. Tallman ◽  
Noel S. Weiss ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Drug Development ◽  
Myeloid Leukemia ◽  
Drug Testing ◽  
Phase 1 ◽  
New Drugs ◽  
Phase 2 ◽  
Novel Drugs ◽  
New Treatments ◽  
Acute Myeloid

AbstractDrugs introduced over the past 25 years have benefitted many patients with acute myeloid leukemia (AML) and provided cure for some. Still, AML remains difficult to treat, and most patients will eventually die from their disease. Therefore, novel drugs and drug combinations are under intense investigation, and promising results eagerly awaited and embraced. However, drug development is lengthy and costs are staggering. While the phase 1–phase 2–phase 3 sequence of clinical drug testing has remained inviolate for decades, it appears intrinsically inefficient, and scientific flaws have been noted by many authors. Of major concern is the high frequency of false-positive results obtained in phase 2 studies. Here, we review features of phase 2 trials in AML that may contribute to this problem, particularly lack of control groups, patient heterogeneity, selection bias, and choice of end points. Recognizing these problems and challenges should provide us with opportunities to make drug development more efficient and less costly. We also suggest strategies for trial design improvement. Although our focus is on the treatment of AML, the principles that we highlight should be broadly applicable to the evaluation of new treatments for a variety of diseases.

Predictivity/Translatability of Toxicities Observed in Nonclinical Toxicology Studies to Clinical Safety Outcomes in Drug Development: Case Examples

2019 ◽  
Vol 39 (2) ◽  
pp. 141-150
Author(s):  
Nicola J. Stagg ◽  
Hanan N. Ghantous ◽  
Robert Roth ◽  
Kenneth L. Hastings
Keyword(s):  
Drug Development ◽  
Annual Meeting ◽  
Clinical Studies ◽  
Early Termination ◽  
New Drugs ◽  
Clinical Safety ◽  
Case Examples ◽  
Palm Springs ◽  
Starting Dose ◽  
Good Concordance

Nonclinical toxicology studies are conducted to characterize the potential toxicities and establish a safe starting dose for new drugs in clinical studies, but the question remains as to how predictable/translatable the nonclinical safety findings are to humans. In many cases, there is good concordance between nonclinical species and patients. However, there are cases for which there is a lack of predictivity or translatability that led to early termination of clinical studies due to unanticipated toxicities or early termination of programs before making it to the clinic due to unacceptable nonclinical toxicities assumed to be translatable. A few case examples of safety findings that are translatable versus safety findings that are not translatable and why they are not translateable were presented as a symposium at the 38th Annual Meeting of the American College of Toxicology in Palm Springs, California, and are discussed in this article.

scholarly journals A Pharmacological Analysis of the Activity and Failure of the Medical Treatment of High-Grade Osteosarcoma

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 141
Author(s):  
Alessandro Comandone ◽  
Antonella Boglione ◽  
Tiziana Comandone ◽  
Fausto Petrelli
Keyword(s):  
Bone Cells ◽  
Age Groups ◽  
The Elderly ◽  
New Drugs ◽  
High Grade ◽  
Secondary Resistance ◽  
Orthopedic Surgeons ◽  
Close Cooperation ◽  
High Grade Osteosarcoma ◽  
Effective Drugs

Osteosarcomas (OSs) are a group of neoplasms originating from bone cells, usually presenting in three specific age groups: children, young adults, and the elderly. High-grade OS is an extremely malignant tumor mainly due to evolution into metastatic disease, usually in the lungs. Survival of these patients has improved since the 1980s thanks to close cooperation between oncologists, oncological surgeons and orthopedic surgeons. Unfortunately, no progress has been made in the last 30 years and new, more effective drugs are needed. This article reviews the biological and pharmacological basis of the treatment of OS. Models of clinical pharmacology of the active drugs, toxic effects and reasons for primary and secondary resistance to old and new drugs are discussed.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Lights and Shadows in Immuno-Oncology Drug Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 691
Author(s):  
Milana Bergamino Sirvén ◽  
Sonia Pernas ◽  
Maggie C. U. Cheang
Keyword(s):  
Drug Development ◽  
Checkpoint Inhibitors ◽  
Late Phase ◽  
New Drugs ◽  
Successful Outcome ◽  
Different Types ◽  
Cancer Types ◽  
Clinical Trial Designs ◽  
Oncology Drug Development ◽  
Critical Aspects

The rapidly evolving landscape of immuno-oncology (IO) is redefining the treatment of a number of cancer types. IO treatments are becoming increasingly complex, with different types of drugs emerging beyond checkpoint inhibitors. However, many of the new drugs either do not progress from phase I-II clinical trials or even fail in late-phase trials. We have identified at least five areas in the development of promising IO treatments that should be redefined for more efficient designs and accelerated approvals. Here we review those critical aspects of IO drug development that could be optimized for more successful outcome rates in all cancer types. It is important to focus our efforts on the mechanisms of action, types of response and adverse events of these novel agents. The use of appropriate clinical trial designs with robust biomarkers of response and surrogate endpoints will undoubtedly facilitate the development and subsequent approval of these drugs. Further research is also needed to establish biomarker-driven strategies to select which patients may benefit from immunotherapy and identify potential mechanisms of resistance.

scholarly journals Characterization and applications of chimeric mice with humanized livers for preclinical drug development

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Chise Tateno ◽  
Yuha Kojima
Keyword(s):  
Liver Function ◽  
Drug Development ◽  
Mass Production ◽  
Human Hepatocytes ◽  
In Vitro Studies ◽  
New Drugs ◽  
Pharmaceutical Companies ◽  
Chimeric Mice ◽  
Preclinical Drug Development

AbstractWe have succeeded in stable mass production of chimeric PXB-mice, whose liver is repopulated by human hepatocytes at a ratio of more than 70%, and we are providing these mice to academia and pharmaceutical companies to support the development of new drugs or studies of liver function. Furthermore, we isolated human hepatocytes, called PXB-cells, from the chimeric mice, and provide them for clients weekly for in vitro studies. In this review, we summarize the existing characterizations of PXB-mice and PXB-cells and their present and future applications.

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