Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Abstract

If disposing of this product, please recycle the paper. Preface to the Third EditionMany issues associated with nonclinical drug safety, as outlined in the various sections of this book, remain outstanding and even persistent and may occur during the process of both drug discovery and drug development.Until recently (15 years ago), the drug discovery and evaluation process was primarily a sequential progression that started with the selection of the most pharmacologically active compound originating from a series of newly synthesized small molecule chemicals by means of the utilization of distinctive biochemical, in vitro and in vivo pharmacological assays.Safety aspects were initially addressed by evaluation of the selected compound at high (suprapharmacological) concentrations in a series of specific in vitro receptor binding studies.These early in vitro secondary pharmacology studies typically evaluate the binding of the selected compound against a broad range panel of targets including receptors, transporters, enzymes, ion channels, and second messengers to assess the pharmacological safety parameters for small molecule drugs.Thus, these assays provide an assessment of potential "off-target" effects of the selected compound.These tests are then followed by conduct of pharmacokinetic studies, which primarily confirm whether the selected compound possesses a suitable drug absorption, distribution, metabolism, and elimination profile.An optimal pharmacokinetic profile ensures that the compound produces sufficient exposure and results in efficacy specific to the intended route of administration.Safety aspects rely predominantly on the conduct of single and repeat dose toxicology studies in both rodent and non-rodent species, which inform drug-associated pathological changes in target organ structure rather than organ function.Both toxicological and pharmacokinetic studies are adapted to the progress of studies during development to support clinical pharmacology and clinical trials.The new edition of this well and broadly accepted reference work contains several innovative and distinguished chapters including novel topics on safety pharmacology and toxicology.Generally, this "sequential" strategy has been abandoned as reflected by the change in content described within this new version of the book for several reasons: Of the possible multitude of negative effects that novel drugs may cause on organ function, e.g., ventricular tachyarrhythmia in the heart, many are detected later in nonclinical studies to inform clinicians early in vii

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