A comprehensive approach for drug safety assessment

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Abstract

A comprehensive, multidisciplinary approach is proposed here for the development of a drug with an acceptable safety profile. Key parameters to be considered for drug safety evaluation based on this comprehensive approach include the following: (1) Pharmacology: Possible toxicity due to drug–target interactions, including interactions with unintended molecular targets, or with molecular targets in unintended organs. (2) Chemistry: Chemical scaffolding and side-chains with safety concerns. (3) Toxicology: Toxicity in animals in vivo, and in relevant animal and human cells in culture. (4) Drug metabolism and pharmacokinetics: Safety concerns due to toxification or detoxification, organ distribution, clearance and pharmacokinetic drug–drug interactions. (5) Risk factors: Physiological, environmental and genetic factors that may enhance a patient's susceptibility. It is proposed that this integrated, multidisciplinary approach to safety evaluation may enhance the accuracy of the prediction of drug safety and thereby the efficiency of drug development.

Introduction

Classical toxicologists rely on Paracelsus’ Principle [1]:

“All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison.”

This principle of toxicology derived in the 15th century is the cornerstone of today's traditional practice of toxicology. Dose–response relationship is the most important data set from which safety is determined. For drugs, safety is estimated based on the therapeutic index, a ratio of the toxic dose to the dose required for efficacy. It is because of Paracelsus’ Principle that toxicologists in general believe that safety can be estimated based on dose–response relationships without a need for mechanistic definition.

This empirical approach to safety evaluation is apparently not adequate, judging from the number of drugs with serious, sometimes fatal adverse effects, which have been erroneously concluded to have an acceptable toxicity profile in preclinical and clinical safety studies. It is proposed here that drug toxicity should be defined based not only on dose–response relationship, but also as a function of pharmacology, chemistry, metabolism, and environmental and genetic risk factors.

Section snippets

A comprehensive approach to drug safety evaluation

The proposed comprehensive approach in drug safety evaluation is based on an integrated, multidisciplinary approach. This comprehensive understanding of drug safety should be applied towards all phases of drug discovery and development, from target identification through clinical trials.

The key scientific disciplines to be included in this comprehensive approach to drug safety evaluation include pharmacology, chemistry, drug metabolism and toxicology. A new discipline of risk factor

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