INTRODUCTION:

The discovery of a new drug^1-7 is not only about its design and synthesis but also its testing, way how it operates and its biological and chemical nature. According to WHO, a drug is defined as “any substance used in a pharmaceutical product that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient” or we can say drugs are chemical substances that are used to prevent or cure diseases in humans, animals and plants. Drugs are used for-

· Supplement for vitamins, mineral salts, and hormones

· Cure disease, like vaccines

· Fight against an infection, like antibiotics

· Temporary blocking of a normal function, like anesthetics

· Detoxification of the body, etc.

The activity of a drug is its pharmacological effect by interfering with biological processes, so no drug is completely safe.

They can act as poisons if taken in excess, for example, overdoses of paracetamol can cause coma and death. Drugs have beneficial as well as non-beneficial effects, like use of cocaine and heroin are strictly controlled. The non-beneficial effects are called side-effects of drug. Their overuse result in the development of resistance to that particular drug by microorganisms, virus as well as patients and called drug resistance.

Procedure followed in Drug design:

Drugs play an important role in human health and having beneficial effects. On the other hand, drugs also have some non-beneficial effects (like use of some drugs may causes side effects), development of resistance (like over use of same drug results pathogens resistant to particular drug) and reduction in effectiveness with time (due to metabolic functioning), that’s why we need new drugs. Although there are some other reasons also, like to improve the treatment of existing disease, to cure new disease and production of safer drug. In easy way we need a new drug to improve effectiveness, reduce toxicity and increase its absorption.

Before to begin drug development process, it will not with the drug but with the identification of a possible target to act upon. This target is protein or metabolic pathway depending on disease and conditions. Once a target is identified and validated, the process to develop an efficient drug begins. The process can be easily understood by following flowchart.

Steps involved in Drug development process:

The process of developing a new drug go through several stages like, discovering, testing, approval and marketing. Now we look through the different steps involved when a compound is approved as a drug.

Research and Development:

The Drug discovery requires teamwork and the members of the team are specialists from various fields, like chemistry, medicine, biochemistry, computerized modelling, toxicology, pharmaceutics, pharmacology, physiology, pathology, etc. The drug development process begins well before clinical testing. It starts with the study regarding chosen disease and identification of target. Then after identification and selection of all possible compounds that hit the target potentially.

Research regarding disease to work on:

The objective of research regarding disease work on will be a detailed assessment of its pathological investigation as well as basic biochemical research. This information is used by the research team to decide the suitable intervention to bring the desired result. Once the point of intervention has been decided, they propose a structure for a lead compound

Identification and validation of therapeutic target:

According to Oxford Dictionary of Biochemistry and Molecular Biology a drug target can be defined as “a biological entity (usually a protein or gene) that interacts with, and whose activity is modulated by, a particular compound. The identification of target needs to find molecule to target or point of intervention in pathways. This identification can be compounds found in the organism (endogenous compounds) or compounds that are not found in the organism (exogenous compounds) that have some biological effect at the intervention site. A target is termed ‘druggable’ if its activity (behavior or function) can be modulated by a therapeutic process. The features of promising drug target are-

1. It has a confirmed role in the pathophysiology or modifying of a disease.

2. It is not evenly distributed throughout the body.

3. It has promising toxicity profile and potential adverse effects

4. Its 3D-structure is available.

Target validation is the process to establish the functional role of the identified target in the disease phenotype. It is the validation of a drug’s efficacy and toxicity in numerous disease-relevant cell models and animal models. Once a therapeutic target is identified, it is verified that it can be successfully reproduced (Reproducibility) and drug’s effect is not altered by variation in cell or tissue cell and mutation in the protein target (therapeutic-target environment).

Identification of lead compound:

In this step researchers made screening of compounds in laboratory to examine their ability to affect identified target and also they don’t interfere with other related targets. The knowledge of disease and biological pathways associated with it result in the identification of therapeutic targets. Once the therapeutic target is identified, researchers have to find one or more leads (chemical compounds or molecules that interact with the therapeutic target with high affinity, efficacy, and selectivity). In the select compounds, its affinity refers to bind with target, its efficacy refers to biochemical or physiologic response and its selectivity refers to the ability to recognize its target without interacting with other related targets. The lead compounds have following characteristics:

1. Designed by molecular modelling or by screening compounds (natural or synthetic)

2. Exhibit therapeutically useful properties

3. Used for drug design and development

Lead modification or lead optimization:

After the discovery of lead compounds, computational and laboratory techniques will be used to refine their molecular structures for greater drug activity and fewer side effects. It is a very long process and done by laboratory experiments as well as computationally, by examining their molecular structures with respect to both drug activity and their side effects. The lead optimisation or modification process is to optimize the structure for best therapeutic effect of the potential drug. It usually involves a series of assumptions and modifications in the primary structure (scaffold) as well as in secondary structure (moieties) of lead compound. The process of lead optimization can be enhanced by using computer software.

“The process of systematic modification and refinement in the structure of the lead compound to get desired properties (maximize the therapeutic effect and minimize side effects)”

The Structure Based Drug Design techniques are especially effective in refining their 3D-structures to improve binding to protein active sites. In addition to affinity, efficacy, and selectivity, a potential drug has many requirements like bioavailability and chemically & metabolically stability. Bioavailability means the available amount of drug at target site. It dependents on its ability to cross biologic barriers (gastrointestinal tract and the blood-brain barrier either by passive or active diffusion) and plasma protein binding (ability to reach sites of action). The lack of absorption, passing through liver metabolism or permeability like blood-brain barrier. During preclinical trials, (NCEs) that are highly potent and selective in vitro are failed significantly in vivo activities because they are unable to reach their sites of action. Now further lead optimization researchers examine their absorption, distribution, metabolism, and excretion (ADME). In vivo activity new chemical entities are examined for drug efficacy and the plasma concentration. Before clinical trials (testing on humans), it is ensured the level of risk against the expected therapeutic benefit. The safety of lead compounds has been evaluated in suitable in vitro and in vivo models (reproductive, immunologic and toxicity effects).

Preclinical Trials:

It is extremely important to complete safety and efficacy evaluation of a test compound before executing clinical trials. Study performed in preclinical phase includes determination of safety, efficacy, tolerability and toxicity of test compound in cell culture or animals. These evaluations whether the test compound is as efficacious and safe in humans or it is stablished that without these preclinical studies it is not possible to strategize clinical trials. These Pharmacological studies (in vitro and in vivo) evaluate biological effect, efficacious dose range and overall potency of the optimized lead compound. Now an understanding about the mechanism of action of the lead compound is being developed by pharmacodynamic studies. The pharmacokinetic studies give detailed insight information on drug distribution in different organs of study animals; post drug treatment; toxicity studies and safety evaluation for the optimized drug. Based on results obtained from preclinical assessments the following profile of drug is made-

a) Duration and frequency of the drug consumption

b) Pharmacological safety

c) Toxicological information

d) Efficacy

e) Absorption, distribution, metabolism, and excretion (ADME) and

f) Strategical designing of clinical trials.

The ideal preclinical model accurately mimics the chosen human disease. This involves a series of experiments either in vitro or in vivo models. In vitro studies are carried out in petri dish and are a relatively fast, simple, and cost efficient. In this researchers utilise cell, tissue and organ cultures, or particular cell components like proteins or biological macromolecules. In vitro studies often provide mechanistic evidence of the investigational drug’s mode of action. In vitro models are less reliable because isolated cells in petri dish may not behave as they would behave within the body. So more sophisticated preclinical models are required to establish the investigating compound’s safety profile before clinical trials. Thus In vivo models, i.e. testing on the complete organism based on various animal models. The mouse the best experimental animal. In vivo studies consider Similar to studies in humans. Animal testing is tightly regulated from local ethical review boards and permission is required to ensure that no unnecessary harm is done to the experimental subjects. The choice of appropriate animal model requires understanding of species-specific physiology and similarity to the target organ, metabolic pathways as well as other considerations. In vivo studies are most frequently performed in a rodent model (mouse, guinea pig, hamster, etc.) and non-rodent model (Mice, rats, and dogs) while testing in primates (monkeys, apes, etc.) is performed occasionally. One of the most popular animal models in pharmaceutical testing is mouse because about 99% of the genomes of mouse and man are highly similar. But species-specific differences in host immune response and drug metabolism affect therapeutic outcomes. Therefore, differences in pharmacokinetics and pharmacodynamics among species are also not negligible.

Toxicity- it is safe:

To determine whether an optimized drug is safe for testing on human, preclinical in vivo and in vitro toxicological studies are performed. It determines a suitable and safe starting dose for clinical trials with respect to treatment duration, schedule, and route of administration. At the same time other studies evaluate carcinogenicity, genotoxicity, and reproductive toxicity. The drug’s genotoxic effect is usually studied in yeast-based in vitro systems (based on potential to induce mutations), carcinogenicity and reproductive toxicity studies typically involve rats. These effects of drug are evident only after prolonged exposure.

Pharmacokinetics and Pharmacodynamics:

The effectiveness of a drug on the body depends on how it causes a change or inhibit the biological activity. It depends on the stability of the drug–substrate complex, while the medical success of the drug depends on whether enough drug molecules bind to affect target molecule or pathway. The drug activity is directly related to its concentration in the aqueous medium in contact with the substrate molecules. The factors affecting this concentration in a biological system are studied in the pharmacokinetic phase of drug action. The pharmacokinetic phase concern with the study of the parameters that control the journey of the drug from its initiation to its point of action. While the pharmacodynamics of drug concern with the chemical nature of the relationship between the drug and its target.

Pharmacokinetics is defined as the study of the time course of drug absorption, distribution, metabolism, and excretion. Its principles are used for the safe and effective therapeutic management of drugs. Pharmacodynamics is defined as the study of correlation between drug concentration and its effect on patients. This specifically refers to the relationship between drug concentration at the site of action and resulting effects with course of time also.

Clinical Trials:

The drug development process is all about a new safe and effective drug. The clinical trials involve human subjects, with basic scientific study same as preclinical research. Before a drug being declared useful or not, clinical trials involve hundreds or thousands of patients. The number of centers able to conduct clinical trials are limited. The number of patients eligible for participating in clinical trials are limited, either due to demographic, comorbidity or incompatible factors and also disease parameters or willingness. While drug development still focused on disease mechanisms. Therefore, a disease population has been targeted during preclinical trials to assess whether the new drug is both safe and effective. It is assessing drug toxicity and the related dosing.

Conducting clinical trials involves:

· Patient’s perspective: The patients are expose to an experimental therapy which usually suffer some degree of toxicity. They trust to the scientific skill and hope for the beneficial results. It is also called human cost.

· Resource’s perspective: To bring a new drug successfully into the market cost of millions. It is also called resource cost.

The successive clinical trials are usually categorized by different phases. These phases are Phase-I, Phase-II, Phase-III and Phase-IV clinical trials which are discussed below:

Phase-I Clinical trials:

In phase I trials a new drug is first introduced into human subjects. With primary goal to assess the safety of the agent and to determine an acceptable dose for further study. It involves assessment of pharmacokinetics as well as pharmacodynamics of drug. The method used depends on drug and disease under consideration.

It typically performed on healthy volunteers. The increasing dose of drug is employed in small successive cohorts of patients. Each cohort is assessed with subsequent dose toxicity levels (limiting toxicity) is not encountered. At each level, the blood and other body fluids are taken for pharmacokinetic studies. In oncology studies (study and treatment of cancer), the first dose is the lowest dose level and based on animal toxicities (10% of the dose that is lethal in 10% of mice, LD-10) and dose increments are often based upon a modified Fibonacci sequence (1,2,3,5,8,13, …). At some point, toxicity is to be excessive and the appropriate dose level is then established. The phase-I studies result to understand acute toxicities. The pharmacokinetic and pharmacodynamic studies suggest the changes in dose or dosing frequency.

Phase-II Clinical trials:

The Phase-II clinical trial studies are conducted to assess the initial activity of a drug against disease and its adverse effects. Additional pharmacokinetic or pharmacodynamic studies are also be conducted. Unlike phase-I studies, phase-II trials typically employ one or occasionally a few dose levels. Larger number of patients are exposed to the drug in order to observe one or more clinical endpoints. In these trials, the physiological parameters may also be assessed in addition to clinical measures (like in heart failure) such as exercise tolerance, Vaccine studies typically involve safety and immune response (both treatment and control groups are under consideration). The investigators should specify the minimal level of drug activity. Phase-II studies would be designed as precursors for phase-III studies.

If a drug effect is seen, then consider whether the effect was sufficiently enough in comparison with existing therapies. If clinical effect was not seen then pharmacokinetic studies are undertaken. The clinical efficacy must be assessed with observed toxicities. More severe toxicities might be acceptable for lifesaving therapies. In phase-II clinical trials, the impact of drug on a disease as well as a better understanding of its toxicity.

Phase-III Clinical trials:

In Phase-III clinical trials typically large randomized studies are designed to demonstrate useful clinical activity against specific disease. The patients are randomizing between different treatment arms. The phase-III clinical trials design is critical both in addressing a specific hypothesis and making a drug useful in clinical practice. The criteria that determine which patients may join the study must be a population that is both generalizable patients’ representative of the disease and to be recognizable disease group.

Phase-IV Clinical trials:

The Phase-IV clinical trial studies are sometimes called pharmacoepidemiologic studies (the study of the utilization and effects of drugs in large numbers of people). Such studies are conducted after a drug has been registered and approved for marketing. It may assess an uncommon toxicity of drug that may be undetectable in Phases-I, Phase-II or Phase-III studies. New methods of drug administration, combinations with other agents, or activity in other diseases also studied, seeking a new marketing indication.

These studies may be conducted in several ways-

· Descriptive studies- sometimes collections of drug toxicities captured over time and may identify new problems. These may range from case studies to series of patients collected by companies or regulatory bodies.

· Randomized studies- to compare an agent to other similar agents and to confirm earlier results.

· Case studies- studies on data after a drug has been accumulated. It will be either unusual side effects or the development of a subsequent disease associated with the drug.

Registration, Approval and Marketing:

After completion of the entire procedure, this particular drug is registered in different countries and after the approval of the authorities, the manufacturers will sell this drug in that country.

CONCLUSION:

The present review of literature represents a road map of designing, synthesizing, testing and marketing of drug. The aim of this article is to make a basic understanding about drug and work culture.

REFERENCES:

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Received on 20.02.2022 Modified on 21.04.2022

Asian J. Res. Pharm. Sci. 2022; 12(3):245-250.

DOI: 10.52711/2231-5659.2022.00043