Perspectives in regulatory science: translational and clinical pharmacology
Publication date: Available online 21 October 2016 Source:Drug Discovery Today: Technologies Author(s): Joseph A. Grillo, Shiew Mei Huang This paper focuses on the role of clinical and translational pharmacology in the drug development and the regulatory process. Contemporary regulatory issues faced by FDA's Office of Clinical Pharmacology (OCP) in fulfilling its mission to advance the science of drug response and translate patient diversity into optimal drug therapy are discussed. Specifically current focus of the following key aspects of the drug development and regulatory science processes are discussed: the OCP vis...
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Translational pharmacokinetic/pharmacodynamic analysis in cancer pharmacology: a tool to maximize the value of antitumor efficacy from tumor bearing mice
Publication date: Available online 21 October 2016 Source:Drug Discovery Today: Technologies Author(s): Harvey Wong, Stephen E. Gould Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis is becoming an increasingly important tool for the identification and selection of new anticancer agents. There are two important elements of effectively using PK/PD analysis to translate preclinical antitumor efficacy from tumor bearing mice (xenografts and allografts) to cancer patients. These two sometimes overlapping elements are termed translation ‘WITHIN’ and ‘ACROSS’ species. Translating ‘WITHIN’ species re...
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Pharmacological considerations for predicting PK/PD at the site of action for therapeutic proteins
Publication date: Available online 22 October 2016 Source:Drug Discovery Today: Technologies Author(s): Weirong Wang, Honghui Zhou For therapeutic proteins whose sites of action are distal to the systemic circulation, both drug and target concentrations at the tissue sites are not necessarily proportional to those in systemic circulation, highlighting the importance of understanding pharmacokinetic/pharmacodynamic (PK/PD) relationship at the sites of action. This review summarizes the pharmacological considerations for predicting local PK/PD and the importance of measuring PK and PD at site of action. Three case exampl...
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Intracerebral microdialysis in blood –brain barrier drug research with focus on nanodelivery
Publication date: Available online 24 October 2016 Source:Drug Discovery Today: Technologies Author(s): Margareta Hammarlund-Udenaes Microdialysis has contributed significantly to advance the understanding of BBB transport of drugs and to reveal key aspects of BBB transport, including quantifying active efflux and active uptake. Microdialysis studies on pharmacokinetic–pharmacodynamic relationships have given in-depth understanding of the processes involved. Recently, nanodelivery to the brain has been investigated with microdialysis, contributing to nanodelivery science by giving quantitative information on the possi...
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies
This article gives a brief overview of the PK and PD of mAbs, factors that influence them, and areas of ongoing inquiry. Current tools and translational approaches to predict the PK/PD of mAbs in humans are also discussed. (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Ultrasound-mediated drug delivery to the brain: principles, progress and prospects
Publication date: Available online 25 October 2016 Source:Drug Discovery Today: Technologies Author(s): Anshuman Dasgupta, Mengjiao Liu, Tarun Ojha, Gert Storm, Fabian Kiessling, Twan Lammers The blood–brain barrier (BBB) limits drug delivery to the central nervous system. When combined with microbubbles, ultrasound can transiently permeate blood vessels in the brain. This approach, which can be referred to as sonoporation or sonopermeabilization, holds significant promise for shuttling large therapeutic molecules, such as antibodies, growth factors and nanomedicine formulations, across the BBB. We here describe ...
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Leverage nonclinical development of bispecifics by translational science
Publication date: Available online 27 October 2016 Source:Drug Discovery Today: Technologies Author(s): Andreas Baumann, Stephanie Fischmann, Guenter Blaich, Matthias Friedrich Bispecific antibody constructs (Bispecifics, bsAbs) may have greater functionality compared to established monoclonal antibodies because they bind to 2 different targets or, potentially, to 2 epitopes on the same target (dual targeting). This may result in enhanced binding avidity with preferential binding to cells that express both targets or binding to targets on different cells. However, development of these next-generation biologics, inclu...
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Exploiting transferrin receptor for delivering drugs across the blood brain barrier
Publication date: Available online 27 October 2016 Source:Drug Discovery Today: Technologies Author(s): Judy Paterson, Carl I. Webster Delivery of large molecule drugs across the blood brain barrier is increasingly being seen as an achievable goal. Several technologies have been described where following peripheral administration the molecules can be detected in the brain. Foremost amongst these technologies are antibodies against the transferrin receptor. Following a burst of publications in the very early twenty first century, excitement seemed to wane as contrary data started to emerge. Over the last few years antib...
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Translational PK/PD of anti-infective therapeutics
Publication date: Available online 28 October 2016 Source:Drug Discovery Today: Technologies Author(s): Chetan Rathi, Richard E. Lee, Bernd Meibohm Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further ...
Source: Drug Discovery Today: Technologies - October 28, 2016 Category: Drugs & Pharmacology Source Type: research
Glutathione conjugation dose-dependently increases brain-specific liposomal drug delivery in vitro and in vivo
Publication date: Available online 13 October 2016 Source:Drug Discovery Today: Technologies Author(s): David Maussang, Jaap Rip, Joan van Kregten, Angelique van den Heuvel, Susanne van der Pol, Burt van der Boom, Arie Reijerkerk, Linda Chen, Marco de Boer, Pieter Gaillard, Helga de Vries The blood–brain barrier (BBB) represents a major obstacle for the delivery and development of drugs curing brain pathologies. However, this biological barrier presents numerous endogenous specialized transport systems that can be exploited by engineered nanoparticles to enable drug delivery to the brain. In particular, conj...
Source: Drug Discovery Today: Technologies - October 13, 2016 Category: Drugs & Pharmacology Source Type: research
Suppression of TH17-mediated pathology through BET bromodomain inhibition
Publication date: Available online 13 August 2016 Source:Drug Discovery Today: Technologies Author(s): Srimoyee Ghosh, Jose M. Lora Epigenetic control of gene expression is enforced in part through histone modifications. Bromodomain and extra terminal domain (BET) proteins function as crucial chromatin readers, responsible for interpretation of the chromatin code in diverse cellular contexts, ultimately impacting gene transcription. BET proteins can play a major role in inflammation by profoundly affecting the biology of the Thelper 17 (TH17) lineage. We summarize recent studies focusing on BET inhibition as a viable t...
Source: Drug Discovery Today: Technologies - August 13, 2016 Category: Drugs & Pharmacology Source Type: research
Regulation of gene expression in human cancers by TRIM24
Publication date: Available online 10 August 2016 Source:Drug Discovery Today: Technologies Author(s): Srikanth Appikonda, Kaushik N. Thakkar, Michelle Craig Barton Tripartite Motif-containing protein 24 (TRIM24) functions as an E3 ligase targeting p53 for ubiquitination, a histone ‘reader’ that interacts with a specific signature of histone post-translational modifications and a co-regulator of nuclear receptor-regulated transcription. Although mouse models of Trim24 depletion suggest that TRIM24 may be a liver-specific tumor suppressor, several studies show that human TRIM24 is an oncogene when aberrantly over e...
Source: Drug Discovery Today: Technologies - August 10, 2016 Category: Drugs & Pharmacology Source Type: research
Development of chemical probes for the bromodomains of BRD7 and BRD9
Publication date: Available online 6 August 2016 Source:Drug Discovery Today: Technologies Author(s): Peter G.K. Clark, Darren J. Dixon, Paul E. Brennan The bromodomain family of proteins are ‘readers’ of acetylated lysines of histones, a key mark in the epigenetic code of gene regulation. Without high quality chemical probes with which to study these proteins, their biological function, and potential use in therapeutics, remains unknown. Recently, a number of chemical ligands were reported for the previously unprobed bromodomain proteins BRD7 and BRD9. Herein the development and characterisation of probes against...
Source: Drug Discovery Today: Technologies - August 7, 2016 Category: Drugs & Pharmacology Source Type: research
Role of BET proteins in castration-resistant prostate cancer
Publication date: Available online 30 July 2016 Source:Drug Discovery Today: Technologies Author(s): Ester Fernandez-Salas, Shaomeng Wang, Arul M Chinnaiyan Castration resistant prostate cancer (CRPC) is a deadly disease with few therapeutic options once patients become resistant to second generation drugs targeting the AR-transcriptional program. The BET-BRD readers of chromatin are key regulators of AR-, ERG-, and c-Myc-mediated transcription in CRPC. BET-BRD inhibitors have demonstrated pre-clinical efficacy in models of CRPC and are currently being evaluated in several clinical trials. These novel drugs have ...
Source: Drug Discovery Today: Technologies - July 30, 2016 Category: Drugs & Pharmacology Source Type: research
Erythropoiesis provides a BRD's eye view of BET protein function
Publication date: Available online 20 July 2016 Source:Drug Discovery Today: Technologies Author(s): Aaron J. Stonestrom, Sarah C. Hsu, Michael T. Werner, Gerd A. Blobel Pharmacologic inhibitors of the bromodomain and extra-terminal motif (BET) protein family are in clinical trials for the treatment of hematologic malignancies, yet the functions of individual BET proteins remain largely uncharacterized. We review the molecular roles of BETs in the context of erythropoiesis. Studies in this lineage have provided valuable insights into their mechanisms of action, and helped define the individual and overlapping f...
Source: Drug Discovery Today: Technologies - July 21, 2016 Category: Drugs & Pharmacology Source Type: research
