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At least 271 records · Page 15Linked to original sources
PubMed1999

Allometric issues in drug development.

The concept of correlating pharmacokinetic parameters with body weight from different animal species has become a useful tool in drug development. The allometric approach is based on the power function, where the body weight of the species is plotted against the pharmacokinetic parameter(s) of interest. Clearance, volume of distribution, and elimination half-life are the three most frequently extrapolated pharmacokinetic parameters. Over the years, many approaches have been suggested to improve the prediction of these pharmacokinetic parameters in humans from animal data. A literature review indicates that there are different degrees of success with different methods for different drugs. Overall, though interspecies scaling requires refinement and better understanding, the approach has lot of potential during the drug development process.

Animals↗
PubMed1993

Ethnopharmacology and future drug development: the North American experience.

The major programs in North America designed to study plants as sources of potential drugs in which ethnomedical information is used to some extent are reviewed. Most of this work is carried out in academic laboratories in the United States; funded primarily from governmental agencies. A few major pharmaceutical companies in the United States are involved in drug development, using plants as sources of starting material, as well as many small start-up firms. These will be identified in the text with their major thrust, where known. Additionally, the NAPRALERT database on natural products will be described with the goal of illustrating how it may be used in the drug development process. Attenders at the Congress were given an opportunity to query the database on-line from Uppsala to Chicago.

Atlantic Islands↗
PubMed2004

Anticancer drug development based on modulation of the Bcl-2 family core apoptosis mechanism.

Cancer cells generally maintain their survival by suppressing apoptosis. Mitochondrial mechanisms are involved in most forms of apoptosis (referred to as mitochondrial apoptosis), and the Bcl-2 family controls apoptosis at the mitochondrion via a balance of the effects of pro- and antiapoptotic members. Antiapoptotic molecules such as Bcl-2 and Bcl-x(L) are often overexpressed in cancer cells and their inhibition is an attractive target for selective killing of tumor cells via induction of apoptosis. Reduction of the levels of these proteins with antisense molecules has shown encouraging experimental and clinical results and there has been some success in developing small-molecule inhibitors. These are likely to be the most productive drug development approaches in the near future. However, growing understanding of the molecular mechanisms involved has identified other potential targets. Cardiolipin is important for the proapoptotic activity of Bcl-2 family members such as Bid, Bax and Bak, and modulation of its metabolism and translocation in mitochondrial membranes could potentially have a strong influence on apoptosis. Post-translational modifications strongly influence the activity of Bcl-2 family members. Several molecules have been identified that bind to Bcl-2 family members and could be intracellular control mechanisms. These mechanisms may yield several drug development targets for the induction of apoptosis. Further research will qualify these targets and, in the longer term, could lead to a more specific means of inducing apoptosis in cancer cells.

Antineoplastic Agents↗
PubMed2003

Quantitative image analysis: software systems in drug development trials.

Multi-dimensional image analysis is being used increasingly to arrive at surrogate end-points for drug development trials. Various imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and ultrasound are used to analyze treatments for diseases such as cancer, multiple sclerosis, osteoarthritis, and Alzheimer's disease. However, extracting information from images can be tedious and is prone to high user variability. The medical image analysis community is moving towards advanced software systems specifically designed for drug development trials. These systems can automatically identify the anatomy of interest in medical images (segmentation methods), can compare the anatomy over time or between patients (registration methods) and allow the quantitative extraction of anatomical features and the integration of the data and results into a database management system, automatically tracking the changes made to the data (audit trail generation). In this article, we present a case study using a prototype system that is used for quantifying multiple sclerosis lesions from multivariate MRI.

Clinical Trials as Topic↗
PubMed2003

Pharmacoproteomics in drug development.

The field of proteomics is taking on increased significance as the relevance of investigating and understanding protein expression in disease and drug development is appreciated. Recent advances in proteomics have been driven by the availability of numerous annotated whole-genome sequences and a broad range of technological and bioinformatic developments that underscore the complexity of the proteome. This review briefly addresses some of the various technologies that comprise Expression Proteomics and Functional Proteomics, citing examples where these emerging approaches have been applied to pharmacology, toxicology, and the development of drugs.

Animals↗
PubMed2001

Emerging role of drug interaction studies in drug development: the good, the bad, and the unknown.

Significant scientific advancements in the last decade have armed researchers with tools to assess drug metabolism and the effects of drugs on metabolic pathways; however, most of this research has focused on cytochrome P450 isozymes. Early delineation of this information aids in the prediction of potential drug-drug interactions, which may ultimately determine whether a compound is pursued in the drug development process. The recent withdrawals of medications such as terfenadine, astemizole, cisapride, and mibefradil from the market demonstrate the relevance of this a priori approach--the risk of drug interactions was largely unrecognized prior to their approval by the Food and Drug Administration (FDA). Drug interaction studies for new drug applications (NDAs) field between 1987 and 1991 were largely in vivo studies with potential coadministered drugs, whereas for NDAs field between 1992 and 1997, the majority of studies involved metabolic mechanisms and in vitro methodology. Despite current limitations in the extrapolation of in vitro drug metabolism data to the in vivo environment, in vitro studies remain the mainstay of initial evaluations in this area primarily because of the high throughput nature of these investigations and the reduced cost compared with in vivo studies. The FDA has published several guidance documents in the area of drug metabolism and drug interaction studies in drug development with suggestions for in vitro as well as in vivo approaches to these investigations. Current and future research will likely focus on in vitro models for cytochrome P450 induction, Phase II metabolism, and drug transporters, and include validation and extrapolation of these approaches in vivo.

Cytochrome P-450 Enzyme System↗
PubMed2004

"Cocktail" approaches and strategies in drug development: valuable tool or flawed science?

There is an increasing interest in the simultaneous administration of several probe substrates to characterize the activity of multiple drug-metabolizing enzymes, the so-called "cocktail" approach. However, this method remains controversial and is being investigated more extensively. No general consensus has emerged on the applicability of this approach in clinical investigation and during drug development. The objective of the article is to review this important yet specialized technique, as well as its merits, drawbacks, and potential application in drug development. Among the two-, three-, four-, five-, and six-drug in vivo cocktails previously evaluated in humans, a variety of substrate probe combinations have been studied. Some probe combinations have been validated not to interact in vivo and have been useful in characterizing drug-drug interaction potential and metabolic enzyme induction in humans. For drug candidates that affect two or more in vitro pathways or are potential gene inducers, the use of a cocktail approach may facilitate the rapid delineation of the drug candidate's drug interaction potential. It may also offer the potential of providing clear guidance on safely conducting larger clinical studies and limiting comedication restrictions to only those likely to be clinically relevant.

Animals↗
PubMed2001

Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies.

In the future, biomarkers will play an increasingly important role in all phases of drug development, including regulatory review. However, only a few of these biomarkers will become established well enough to serve in regulatory decision making as surrogate endpoints, thereby substituting for traditional clinical endpoints. Even generally accepted surrogate endpoints are unlikely to capture all the therapeutic benefits and potential adverse effects a drug will have in a diverse patient population. Accordingly, combinations of biomarkers probably will be needed to provide a more complete characterization of the spectrum of pharmacologic response. In the future, pharmacogenomic approaches, including those based on differential expression of gene arrays, will provide panels of relevant biomarkers that can be expected to transform the drug development process.

Animals↗
PubMed1998

Discussion on early clinical drug development in the target population with respect to the field of reproductive endocrinology.

The study populations taking part in early clinical drug development of reproductive endocrine treatments are discussed. After having compared subjects in phase I studies with subsequent target populations, the question was posed as to whether the inclusion of the later target population could accelerate the developmental process. This applies only to certain specific clinical questions that are posed in phase I studies. From the authors' perspective, the key goal of rapid and well-structured early drug development is to be attained by using reliable surrogate markers that are able to reflect the clinical effects.

Adult↗
PubMed2000

Clinical trial simulation in drug development.

Clinical trial simulation is the application of old technologies, e.g., Monte Carlo simulation, to a new problem, that problem being how to maximize the information content obtained during the drug development process with an intent to have the greatest chance of "success" in a clinical trial. When the information content of the drug is high, then simulation provides a method to synthesize that information into a coherent package that indicates the sponsor has good control over the pharmacology of the drug. From a purely financial point of view, what simulation offers pharmaceutical companies is the possibility of reducing the number of required studies, maximizing the chances for success in a clinical trial, and possibly shortening development time; all outcomes which will reduce drug development costs. The purpose of this paper is to introduce clinical trial simulation to the reader by discussing its potential in drug development, to briefly review the literature, and to make recommendations and caveats regarding its use.

Clinical Trials as Topic↗
PubMedDate not supplied

Pharmacogenetic and pharmacogenomic studies. Impact on drug discovery and drug development.

The topics discussed in this article are concerned with studying genomic polymorphism and identifying new therapeutic targets, the role of genetics in preclinical and clinical drug development, and cultural, regulatory and logistical aspects of the development of pharmacogenetics in France. The conclusions are that from a physiological, biochemical or genomic point of view, the study of human genetic polymorphism has obvious potential value for drug development, because it can help to identify new therapeutic targets, and to predict drug efficacy and tolerability more effectively. There are already several examples of the latter approach, which relies on studying the genetic variability of enzymes involved in drug metabolism, and that of the effector molecules of the pharmacological activity. Pharmacogenetics could eventually make it possible to personalize drug treatments, as methods for analysing genes are simplified and their cost reduced. To help attain this still far-off goal, certain recommendations have been proposed.

Drug Design↗
PubMed2006

Drug development in oncology: classical cytotoxics and molecularly targeted agents.

There is an apparent need to improve the speed and efficiency of oncological drug development. Furthermore, strategies traditionally applied to the development of standard cytotoxic chemotherapy may not be appropriate for molecularly targeted agents. This is particularly the case for exploratory Phase 1 and 2 trials. Conventional approaches to determine dose based on maximum tolerability and efficacy based on objective tumour response may not be suitable for targeted agents, since many of them have a wide therapeutic index and inhibit tumour growth without demonstrable cytotoxicity. Instead, exploratory trials of targeted agents may have to focus on other end-points such as pharmacological effects and disease stabilization. Thus, there is an increasing interest in making the best possible use of biomarkers and pharmacogenomics in early phases of drug development.

Antineoplastic Agents↗
PubMed2003

Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop.

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.

Clinical Trials as Topic↗
PubMed2005

Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report.

Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs. The 2003 American Association of Pharmaceutical Sciences/Clinical Ligand Assay Society Biomarkers Workshop (Salt Lake City, UT, USA, October 24-25, 2003) addressed key issues in biomarker research, with an emphasis on the validation and implementation of biochemical biomarker assays, covering from preclinical discovery of efficacy and toxicity biomarkers through clinical and postmarketing implementation. This summary report of the workshop focuses on the major issues discussed during presentations and open forums and noted consensus achieved among the participants on topics from nomenclature to best practices. For example, it was agreed that because reliable and accurate data provide the basis for sound decision making, biomarker assays must be validated in a manner that enables the creation of such data. The nature of biomarker measurements often precludes direct application of regulatory guidelines established for clinical diagnostics or drug bioanalysis, and future guidance on biomarker assay validation should therefore be adaptable enough that validation criteria do not stifle creative biomarker solutions.

Biological Assay↗
PubMed1989

A phased approach to drug development.

It is possible in the UK to carry out a phased approach to drug development that is designed to assist in the selection of a candidate drug for development from a series of compounds; minimize the amount of animal work (toxicological and metabolic) necessary to permit early evaluation in man; introduce a more rational basis for decision making by setting criteria that must be satisfied before entry can be made into the next phase of development; obtain safety, pharmacokinetic, and possibly dynamic data in man within about 16 months of receipt of the compound.

Animals↗
PubMed2002

Dedicated small animal scanners: a new tool for drug development?

Nuclear imaging techniques can provide information about the time course of uptake, the spatial distribution, and the functional effects of a drug in the human body. Recently, PET has also acquired the potential to affect the drug development process during a very early stage, when a drug is undergoing animal testing. The development of dedicated small animal scanners with high resolution has made it possible to assess the time course of uptake of a drug within a single animal, providing that the drug is labelled with a positron-emitting isotope. Dedicated small animal scanners may therefore prove to be very useful, especially in those parts of the drug development process that require a longitudinal study design. However, in the case of receptor and enzyme studies, there may be pharmacological constraints and specific radioactivity of the radiopharmaceuticals may become an important issue. This paper will assess the potential and also the limitations of high-resolution PET in animal testing of therapeutic drugs.

Animals↗
PubMed2000

From oncogene to drug: development of small molecule tyrosine kinase inhibitors as anti-tumor and anti-angiogenic agents.

The confluence of two distinct but related activities in the past 10 years has dramatically accelerated efforts towards the discovery and development of novel drugs to treat cancer. The first is a rapidly emerging understanding that a number of distinct tyrosine kinases play roles in diverse but fundamentally important aspects of tumor progression (growth, survival, metastasis and angiogenesis). The second is the discovery that small molecule compounds have the capacity to potently and selectively inhibit the biochemical function of tyrosine kinases by competing for ATP binding at the enzyme catalytic site. These observations have been conjoined in major efforts to bring forward into clinical development novel cancer drugs with the potential to provide both clinical efficacy and improved tolerability. The focus of this review is on the development of small molecule tyrosine kinase inhibitors, and does not extend to other approaches that could be applied to disrupt the same pathways in clinical tumors (receptor and/or ligand-competitive antibodies, intrabodies, antisense ribonucleotides, ribozymes, phosphatase inhibitors or SH2/SH3-directed agents). Selected tyrosine kinase inhibitors, known or believed to be in development in cancer treatment trials, are summarized as are some of the key issues that must be addressed if these compounds are to be developed into clinically useful cancer chemotherapeutic agents.

Adenosine Triphosphate↗