In Vitro Preclinical Studies

In drug development, preclinical development is the phase of research that begins before clinical trials, during which important feasibility, iterative testing, and drug safety data are collected. The primary objectives of the preclinical study are to determine the initial safe dose for the first human trial and to evaluate the potential toxicity of the product.

Preclinical testing is the link between drug discovery and patient availability. They can provide evidence of the biological effects of compounds, usually including in vitro and in vivo studies. For in vitro studies, cell lines from human or non-human animals are used and new drugs under development are introduced in petri dishes or test tubes. In vitro studies have many benefits. The first and most obvious benefit is that they do not cause harm to animals or humans derived from cell cultures, and they do not have the disadvantages of animal testing. Other benefits include relatively inexpensive surgeries, they are also reliable and effective.

Fig.1 Preclinical studies toward investigational new drug filings. (Reiner, 2017)

In Vitro Models-Studying the Drug in a Petri Dish

Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics (what the drug does to the body) (PD), pharmacokinetics (what the body does to the drug) (PK), ADME, and toxicology testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans.

• ADME and Bioanalysis in the Drug Discovery

High-throughput in vitro ADME (absorption, distribution, metabolism, and excretion) screening (HT-ADME) has been widely adopted as an essential part of lead optimization for synthetic molecules since around the year 2000. HT-ADME screening usually consists of in vitro assay suites that assess compound properties (or liabilities) such as metabolism, permeability, drug-drug-interactions, physicochemical properties, and also toxicities. The HT-ADME assay portfolio continues to expand in emerging areas such as drug-transporter interactions, early soft spot identification, and ADME screening of peptide drug candidates.

• Pharmacokinetic/Pharmacodynamic (PK/PD) Study

The PK/PD analysis can be applied in drug development to scale from animal studies, establish the optimal dosing regimens in clinical trials or describe the kinetic and dynamic relation for new drugs, as regulatory agencies have started to require. PK/PD modeling and simulation has become a widely used methodology to improve the efficiency and quality of decision making in later-stage clinical drug development. PK/PD for translational research is a relatively new area in drug discovery and, to date, has mainly been developed in academic research. A key aim of translational PK/PD is to support predictions about probable drug activity across species, especially at the preclinical-clinical interface.

• Safety and Toxicity Assessment

Drug safety is a major challenge in bringing new drugs to market. To determine whether a drug is safe for testing in human subjects, preclinical toxicology studies are performed to identify the treatment regimen associated with the least degree of toxicity and thus determine a suitable and safe starting dose for clinical trials. Drug toxicity determination is a major step in drug design and involves identifying the adverse events (AEs) of chemicals on humans, plants, animals, and the environment.

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Reference

1. Reiner, A.T.; et al. Concise Review: Developing Best-Practice Models for the Therapeutic Use of Extracellular Vesicles. Stem Cells Transl Med. 2017 Aug;6(8):1730-1739.