Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

Abstract

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

Are Phage Lytic Proteins the Secret Weapon To Kill Staphylococcus aureus ?

“…Before a new drug can be used for therapeutic purposes in humans, several preclinical and clinical trials have to be performed. Preclinical studies include pharmacokinetics, ADME (absorption, distribution, metabolism, and elimination), and other safety-related parameters, such as genotoxicity, mutagenicity, safety pharmacology, and general toxicology ( 56 ). Among all these requirements, only a few have already been met for S. aureus phage lytic proteins.…”

“…Similarly, a synergistic effect between LysH5 and the bacteriocin nisin was observed for the elimination of S. aureus in milk ( 63 ). Synergy between phage lytic proteins and other antimicrobials might be explained by an initial weakening of the cell wall caused by the endolysin, which might facilitate the subsequent entry of the antibiotic or bacteriocin inside the bacterial cell ( 56 ).…”

Bioactive properties: enhancement of hepatoprotective, antioxidant and DNA damage protective effects of golden grey mullet protein hydrolysates against paracetamol toxicity

“…9 The past decade has also witnessed intense interest in functional foods or dietary photochemical which can inuence the pharmacological activity of drugs and their toxicities by modifying metabolism system, including drug-metabolizing enzymes and transporters. 10 In the pharmaceutical industry, liver, a vital organ in the body responsible for metabolizing and detoxication of substances, 11 is one of the routinely assessed organs during preclinical safety evaluations. Indeed several biological compounds with antioxidant properties proved effective in protecting the liver against deleterious effects of paracetamol overdose.…”

Engineering in vitro models of hepatofibrogenesis

“…This is because animal models combine the native ECM microenvironment, different cell types, as well as oxygen and nutritional flows [95,96]. Limitations of using animal models are numerous; such as the non-human origin, significant differences in metabolic capacities, cytochrome P450 isoforms activity, interspecies physiologies, drug bioavailability and half-life, and disease adaptive mechanisms [97][98][99][100]. Many of these compounds fail due to undesirable toxicity and/or lack of clinical effectiveness, which is usually observed during the most expensive phase of clinical development i.e.…”