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Drug Development Process (drug + development_process)
Selected AbstractsAccelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosingDRUG DEVELOPMENT RESEARCH, Issue 1 2007Matthew A. McLean Abstract Microdosing of experimental therapeutics in humans offers a number of benefits to the drug development process. Microdosing, conducted under an exploratory Investigational New Drug (IND) application, entails administration of a sub-pharmacological dose of a new chemical entity (NCE) that allows for early evaluation of human pharmacokinetics. Such information can be pivotal for: (1) selecting a compound for full drug development from a small group of candidates; (2) defining the amount of material needed for early development; and (3) setting the initial Phase I dose regimen in humans. Appropriate safety studies must be conducted to support microdosing in humans, but the requirements are generally less extensive than those needed to support a traditional IND. To date, microdosing has not been broadly applied by the pharmaceutical industry due to concerns about analytical sensitivity and the possibility of non-linear pharmacokinetics at extremely low doses. The primary method for detecting analytes following microdosing until now has been accelerator mass spectrometry, which is expensive, not generally available, and requires test agents to be radiolabeled. Presented in this report is an example of pharmacokinetics analysis using LC/MS/MS following microdosing of an experimental agent in cynomolgus monkeys. The results show good linearity in plasma pharmacokinetics for oral doses of 10,mg/kg (therapeutic dose) and 0.0005,mg/kg (microdose) of the test agent. The results also demonstrate the feasibility of applying standard laboratory analytics to support microdosing in humans and raise the possibility of establishing an animal model to screen for compounds having non-linear pharmacokinetics at low dose levels. Drug Dev. Res. 68:14,22, 2007. © 2007 Wiley-Liss, Inc. [source] Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic propertiesJOURNAL OF APPLIED TOXICOLOGY, Issue 3 2009Sebastian Polak Abstract The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug,hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC50) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC50 values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC50 data available in accessible scientific literature to provide a high-quality data set for further studies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Multivariate methods in pharmaceutical applicationsJOURNAL OF CHEMOMETRICS, Issue 3 2002Jon Gabrielsson Abstract This review covers material published within the field of pharmacy in the last five years. Articles concerning experimental design, optimization and applications of multivariate techniques have been published, from factorial designs to multivariate data analysis, and the combination of the two in multivariate design. The number of publications on this topic testifies to the good results obtained in the studies. Much of the published material highlights the usefulness of experimental design, with many articles dealing with optimization, where much effort is spent on getting useful results. Examples of multivariate data analysis are comparatively few, but these methods are gaining in use. The employment of multivariate techniques in different applications has been reviewed. The examples in this review represent just a few of the possible applications with different aims within pharmaceutical applications. A number of companies are using experimental design as a standard tool in preformulation and in combination with response surface modeling. The properties of e.g. a tablet can be optimized to fulfill a well-specified aim such as a specific release profile, hardness, disintegration time etc. However, none of the companies apply multivariate methods in all steps of the drug development process. As this is still very much a growing field, it is only a question of time before experimental design, optimization and multivariate data analysis are implemented throughout the entire formulation process, from performulation to multivariate process control. Copyright ©,2002 John Wiley & Sons, Ltd. [source] Pharmacokinetic aspects of biotechnology productsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2004Lisa Tang Abstract In recent years, biotechnologically derived peptide and protein-based drugs have developed into mainstream therapeutic agents. Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development in the global pharmaceutical industry. Pharmacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as protein nutrients. The first challenge frequently comes from a lack of sophistication in various analytical techniques for the quantification of peptide and protein drugs in biological matrices. However, advancements in bioassays and immunoassays,along with a newer generation of mass spectrometry-based techniques,can often provide capabilities for both efficient and reliable detection. Selection of the most appropriate route of administration for biotech drugs requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes. Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure to exert the intended pharmacological response. This poses a potential problem, especially for large protein drugs, with their typically limited distribution space. Binding phenomena and receptor-mediated cellular uptake may further complicate this issue. Elimination processes,a critical determinant for the drug's systemic exposure,may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Pharmacokinetic/pharmacodynamic (PK/PD) correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms. Extensive use of pharmacokinetic and exposure/response concepts in all phases of drug development has in the past been identified as a crucial factor for the success of a scientifically driven, evidence-based, and thus accelerated drug development process. Thus, PK/PD concepts are likely to continue and expand their role as a fundamental factor in the successful development of biotechnologically derived drug products in the future. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2184,2204, 2004 [source] Blood,brain barrier efflux transportJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2003Pamela L. Golden Abstract Efflux transport at the blood,brain barrier (BBB) limits the brain tissue exposure to a variety of potential therapeutic agents, including compounds that are relatively lipophilic and would be predicted to permeate the endothelial lining of the brain microvasculature. Recent advances in molecular and cell biology have led to identification of several specific transport systems at the blood,brain interface. Refinement of classical pharmacokinetic experimentation has allowed assessment of the structural specificity of transporters, the impact of efflux transport on brain tissue exposure, and the potential for drug,drug interactions at the level of BBB efflux transport. The objective of this minireview is to summarize efflux transporter characteristics (location, specificity, and potential inhibition) for transport systems identified in the BBB. A variety of experimental approaches available to ascertain or predict the impact of efflux transport on net brain tissue uptake of substrates also are presented. The potential impact of efflux transport on the pharmacodynamics of agents acting in the central nervous system are illustrated. Finally, general issues regarding the role of identifying efflux transport as part of the drug development process are discussed. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1739,1753, 2003 [source] The effect of disorder on the chemical reactivity of an organic solid, tetraglycine methyl ester: Change of the reaction mechanismJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2002Evgenyi Shalaev Abstract Many drugs undergo chemical changes in the solid state, and understanding chemical reactivity of organic crystals is a critical factor in the drug development process. In this report, the impact of milling on the thermal chemical reactivity of an organic solid, tetraglycine methyl ester, was studied using DSC, isothermal calorimetry, chemical analysis (HPLC and insoluble residue determination), and powder X-ray diffraction. Significant changes in both X-ray diffraction patterns and DSC curves were detected after very brief milling (5 s). The changes were interpreted as the formation of a disordered phase. The disordered phase was tentatively identified as a crystal mesophase that combines properties of both crystalline (i.e., long-range order) and amorphous (i.e., glass transition) states. In the disordered material, the reaction mechanism changed from the methyl transfer reaction, which was observed in the intact crystal, to a polycondensation reaction when the reaction was performed at 165°C. Such changes in the reaction mechanism occurred in materials milled for >,30 s. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:584,593, 2002 [source] Pharmacokinetic/pharmacodynamic studies in drug product developmentJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2002Bernd Meibohm Abstract In the quest of ways for rationalizing and accelerating drug product development, integrated pharmacokinetic/pharmacodynamic (PK/PD) concepts provide a highly promising tool. PK/PD modeling concepts can be applied in all stages of preclinical and clinical drug development, and their benefits are multifold. At the preclinical stage, potential applications might comprise the evaluation of in vivo potency and intrinsic activity, the identification of bio-/surrogate markers, as well as dosage form and regimen selection and optimization. At the clinical stage, analytical PK/PD applications include characterization of the dose,concentration,effect/toxicity relationship, evaluation of food, age and gender effects, drug/drug and drug/disease interactions, tolerance development, and inter- and intraindividual variability in response. Predictive PK/PD applications can also involve extrapolation from preclinical data, simulation of drug responses, as well as clinical trial forecasting. Rigorous implementation of the PK/PD concepts in drug product development provides a rationale, scientifically based framework for efficient decision making regarding the selection of potential drug candidates, for maximum information gain from the performed experiments and studies, and for conducting fewer, more focused clinical trials with improved efficiency and cost effectiveness. Thus, PK/PD concepts are believed to play a pivotal role in streamlining the drug development process of the future. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:18,31, 2002 [source] Prediction of pharmacokinetics prior to in vivo studies.JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2002Abstract In drug discovery and nonclinical development the volume of distribution at steady state (Vss) of each novel drug candidate is commonly determined under in vivo conditions. Therefore, it is of interest to predict Vss without conducting in vivo studies. The traditional description of Vss corresponds to the sum of the products of each tissue:plasma partition coefficient (Pt:p) and the respective tissue volume in addition to the plasma volume. Because data on volumes of tissues and plasma are available in the literature for mammals, the other input parameters needed to estimate Vss are the Pt:p's, which can potentially be predicted with established tissue composition-based equations. In vitro data on drug lipophilicity and plasma protein binding are the input parameters used in these equations. Such a mechanism-based approach would be particularly useful to provide first-cut estimates of Vss prior to any in vivo studies and to explore potential unexpected deviations between sets of predicted and in vivoVss data, when the in vivo data become available during the drug development process. The objective of the present study was to use tissue composition-based equations to predict rat and human Vss prior to in vivo studies for 123 structurally unrelated compounds (acids, bases, and neutrals). The predicted data were compared with in vivo data obtained from the literature or at Roche. Overall, the average ratio of predicted-to-experimental rat and human Vss values was 1.06 (SD,=,0.817, r,=,0.78, n,=,147). In fact, 80% of all predicted values were within a factor of two of the corresponding experimental values. The drugs can therefore be separated into two groups. The first group contains 98 drugs for which the predicted Vss were within a factor of two of those experimentally determined (average ratio of 1.01, SD,=,0.39, r,=,0.93, n,=,118), and the second group includes 25 other drugs for which the predicted and experimental Vss differ by a factor larger than two (average ratio of 1.32, SD,=,1.74, r,=,0.42, n,=,29). Thus, additional relevant distribution processes were neglected in predicting Vss of drugs of the second group. This was true especially in the case of some cationic-amphiphilic bases. The present study is the first attempt to develop and validate a mechanistic distribution model for predicting rat and human Vss of drugs prior to in vivo studies. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:129,156, 2002 [source] Review: Neutrophil gelatinase-associated lipocalin: A troponin-like biomarker for human acute kidney injuryNEPHROLOGY, Issue 4 2010PRASAD DEVARAJAN ABSTRACT Acute kidney injury (AKI) is a common and serious condition, the diagnosis of which currently depends on functional markers such as serum creatinine measurements. Unfortunately, creatinine is a delayed and unreliable indicator of AKI. The lack of early biomarkers of structural kidney injury (akin to troponin in acute myocardial injury) has hampered our ability to translate promising experimental therapies to human AKI. Fortunately, understanding the early stress response of the kidney to acute injuries has revealed a number of potential biomarkers. The discovery, translation and validation of neutrophil gelatinase-associated lipocalin (NGAL), possibly the most promising novel AKI biomarker, is reviewed. NGAL is emerging as an excellent stand-alone troponin-like structural biomarker in the plasma and urine for the early diagnosis of AKI, and for the prediction of clinical outcomes such as dialysis requirement and mortality in several common clinical scenarios. The approach of using NGAL as a trigger to initiate and monitor therapies for AKI, and as a safety biomarker when using potentially nephrotoxic agents, is also promising. In addition, it is hoped that the use of sensitive and specific biomarkers such as NGAL as endpoints in clinical trials will result in a reduction in required sample sizes, and hence the cost incurred. Furthermore, predictive biomarkers like NGAL may play a critical role in expediting the drug development process. However, given the complexity of AKI, additional biomarkers (perhaps a panel of plasma and urinary biomarkers) may eventually need to be developed and validated for optimal progress to occur. [source] Application of Genomics in Preclinical Drug Safety EvaluationBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2006Peter G. Lord Toxicologists have traditionally gathered pathological, morphological, chemical and biochemical information from in vivo studies of preclinical species in order to assess drug safety and to determine how new drugs can be safely administered to the human patient population. In recent years the emerging "-omics" technologies have been developed and integrated into preclinical studies in order to better assess drug safety by gaining information on the cellular and molecular events underlying adverse drug reactions. Genomics approaches in particular have become readily available and are being applied in several stages of drug development. The burgeoning literature on what has become known as "toxicogenomics" has for the most part highlighted successful applications of gene expression profiling in predictive toxicology, enabling decisions to be made on the developability of a compound early in the drug development process. It is also becoming apparent that toxicogenomic approaches are good starting points to develop experiments designed to gain a mechanistic insight into drug toxicities within and across species. Gene expression arrays permit the measurement of responses of essentially all the genes in the entire genome to be monitored, and knowledge of the function of the genes affected can identify the potential mechanisms to then be confirmed using conventional biochemical, toxicological and pathological approaches. As toxicologists put these technologies into practice they build up a knowledge base to better characterize toxicities at the molecular level and to make the search for much needed, novel biomarkers of toxicity more achievable. [source] Measurement of xenobiotics in saliva: is saliva an attractive alternative matrix?BIOMEDICAL CHROMATOGRAPHY, Issue 1 2009Case studies, analytical perspectives Abstract The use of saliva for measuring xenobiotic concentrations has been practiced for a number of years. While the use of saliva has been generally reserved for the analysis of diagnostic and forensic/toxicology samples, attempts have been made to further enhance the value of saliva as an alternate matrix to those of plasma and serum. It is understood that saliva represents a handy tool for therapeutic drug monitoring (TDM) as it offers certain distinctive advantages. This scope of this review encompasses the following: (a) a comprehensive view of saliva as an alternate matrix for either plasma or serum to understand the pharmacokinetic/pharmacodynamic (PK/PD) characteristics; (b) an account of the factors contributing to the observed variability in salivary monitoring; (c) a tabular compilation of diverse case studies of xenobitoics belonging to different therapeutic classes with emphasis on assay methodology and applicable analytical/biopharmaceutical/pharmacokinetic findings; (d) relevant thoughts on assay procedures as they relate to salivary monitoring; and (e) some representative case studies highlighting the new thinking on the use of saliva outside of traditional TDM. Overall, based on the review, saliva represents a valuable TDM tool for a number of xenobiotics. While parent compound and phase I metabolite(s) for many xenobiotics have been generally quantifiable in saliva, phase II metabolites have not generally been detected in saliva. Therefore saliva samples could also be used to answer some specific PK/PD questions during the drug development process, if applicable. However, the development and validation of the assay in saliva needs to be carried out carefully with particular focus on proper sample collection, processing and storage to ensure the stability of the xenobiotics and with the same rigor as applied to plasma, serum and urine matrices. Copyright © 2008 John Wiley & Sons, Ltd. [source] Design Of Clinical Pharmacology TrialsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2001Stephen B Duffull SUMMARY 1. There are a variety of methods that could be used to increase the efficiency of the design of experiments. However, it is only recently that such methods have been considered in the design of clinical pharmacology trials. 2. Two such methods, termed data-dependent (e.g. simulation) and data-independent (e.g. analytical evaluation of the information in a particular design), are becoming increasingly used as efficient methods for designing clinical trials. These two design methods have tended to be viewed as competitive, although a complementary role in design is proposed here. 3. The impetus for the use of these two methods has been the need for a more fully integrated approach to the drug development process that specifically allows for sequential development (i.e. where the results of early phase studies influence later-phase studies). 4. The present article briefly presents the background and theory that underpins both the data-dependent and -independent methods with the use of illustrative examples from the literature. In addition, the potential advantages and disadvantages of each method are discussed. [source] | |||||||||||||