ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity.

[1]  Dominic P. Williams,et al.  Idiosyncratic toxicity: the role of toxicophores and bioactivation. , 2003, Drug discovery today.

[2]  Y. Sugiyama,et al.  Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier. , 1996, The Journal of pharmacology and experimental therapeutics.

[3]  C. Daumas-Duport,et al.  Evaluation of Drug Penetration into the Brain: A Double Study by in Vivo Imaging with Positron Emission Tomography and Using an in Vitro Model of the Human Blood-Brain Barrier , 2006, Journal of Pharmacology and Experimental Therapeutics.

[4]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

[5]  J. Uetrecht.  Idiosyncratic drug reactions: past, present, and future. , 2008, Chemical research in toxicology.

[6]  R. Moreno-Sánchez,et al.  Multisite control of the Crabtree effect in ascites hepatoma cells. , 2001, European journal of biochemistry.

[7]  Yvonne Will,et al.  Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[8]  D. Scherman,et al.  Functional Expression of P‐Glycoprotein in an Immortalised Cell Line of Rat Brain Endothelial Cells, RBE4 , 1996, Journal of neurochemistry.

[9]  Stephen H. Friend,et al.  How molecular profiling could revolutionize drug discovery , 2005, Nature Reviews Drug Discovery.

[10]  Xingrong Liu,et al.  Strategies to optimize brain penetration in drug discovery. , 2005, Current opinion in drug discovery & development.

[11]  E. Ezan,et al.  A co-culture-based model of human blood–brain barrier: application to active transport of indinavir and in vivo–in vitro correlation , 2002, Brain Research.

[12]  J. Ryan,et al.  Translational research in central nervous system drug discovery , 2005, NeuroRX.

[13]  Eric D. Adler,et al.  Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population , 2008, Nature.

[14]  H. Kubinyi.  Drug research: myths, hype and reality , 2003, Nature Reviews Drug Discovery.

[15]  Masami Niwa,et al.  Permeability Studies on In Vitro Blood–Brain Barrier Models: Physiology, Pathology, and Pharmacology , 2005, Cellular and Molecular Neurobiology.

[16]  R. Chandra,et al.  Lead-induced phospholipidosis and cholesterogenesis in rat tissues. , 2009, Chemico-biological interactions.

[17]  K I Kaitin,et al.  Obstacles and Opportunities in New Drug Development , 2008, Clinical pharmacology and therapeutics.

[18]  Joe K. Stephens.  Panel faults Pfizer in '96 clinical trial in Nigeria. , 2006, The Washington post.

[19]  J. H. Beijnen,et al.  Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs , 1994, Cell.

[20]  R. Woosley,et al.  Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin , 1992, Clinical pharmacology and therapeutics.

[21]  W H Oldendorf,et al.  Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. , 1970, Brain research.

[22]  C. Crone,et al.  THE PERMEABILITY OF CAPILLARIES IN VARIOUS ORGANS AS DETERMINED BY USE OF THE 'INDICATOR DIFFUSION' METHOD. , 1963, Acta physiologica Scandinavica.

[23]  L. Mandell,et al.  Comparative Tolerability of the Newer Fluoroquinolone Antibacterials , 1999, Drug safety.

[24]  W. Elmquist,et al.  Application of Microdialysis in Pharmacokinetic Studies , 1997, Pharmaceutical Research.

[25]  Michael L Shuler,et al.  Incorporation of 3T3‐L1 Cells To Mimic Bioaccumulation in a Microscale Cell Culture Analog Device for Toxicity Studies , 2008, Biotechnology progress.

[26]  N. Kaplowitz,et al.  Role of innate immunity in acetaminophen-induced hepatotoxicity , 2006, Expert opinion on drug metabolism & toxicology.

[27]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[28]  C. Laggner,et al.  Why drugs fail--a study on side effects in new chemical entities. , 2005, Current pharmaceutical design.

[29]  Sean Ekins,et al.  Techniques: application of systems biology to absorption, distribution, metabolism, excretion and toxicity. , 2005, Trends in pharmacological sciences.

[30]  C. Lipinski.  Drug-like properties and the causes of poor solubility and poor permeability. , 2000, Journal of pharmacological and toxicological methods.

[31]  Richard M Walmsley,et al.  High-specificity and high-sensitivity genotoxicity assessment in a human cell line: validation of the GreenScreen HC GADD45a-GFP genotoxicity assay. , 2006, Mutation research.

[32]  Yvonne Will,et al.  The significance of mitochondrial toxicity testing in drug development. , 2007, Drug discovery today.

[33]  S. Rapoport,et al.  An in situ brain perfusion technique to study cerebrovascular transport in the rat. , 1984, The American journal of physiology.

[34]  P. Bernardi,et al.  High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening , 2006, Archives of Toxicology.

[35]  D. Wortham,et al.  Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. , 1993, JAMA.

[36]  A. Minn,et al.  Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. , 1999, Cellular and molecular biology.

[37]  R. W. Hansen,et al.  The price of innovation: new estimates of drug development costs. , 2003, Journal of health economics.

[38]  P Smith,et al.  Concordance of the toxicity of pharmaceuticals in humans and in animals. , 2000, Regulatory toxicology and pharmacology : RTP.

[39]  Mesens Natalie,et al.  A 96-well flow cytometric screening assay for detecting in vitro phospholipidosis-induction in the drug discovery phase. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[40]  W. Pardridge,et al.  Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. , 1990, The Journal of pharmacology and experimental therapeutics.

[41]  Neil Kaplowitz,et al.  Idiosyncratic drug hepatotoxicity , 2005, Nature Reviews Drug Discovery.

[42]  Draft Guidance,et al.  Guidance for Industry Drug Interaction Studies — Study Design , Data Analysis , and Implications for Dosing and Labeling DRAFT GUIDANCE , 2006 .