Pre-clinical Pharmacology and Clinical Pharmacology - An Overview

The aims of experimental pharmacology are discovery and development of the new drugs, study of the mechanism and site of action of different drugs and study the toxicity effect of a drug.  Experimental pharmacology consists of preclinical study and clinical study.

Figure 1: Types of experimental Pharmacology

Preclinical pharmacology

Preclinical studies involve in-vivo and in-vitro experiments using wide range of doses of the sample drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug (IND).

In-vivo (animal testing) study is used to measure: how much of a drug is absorbed into the blood, how it is broken down chemically in the body, the toxicity of the drug and its breakdown products or metabolites, and how quickly the drug and its metabolites are excreted from the body. Short-term testing in animals ranges in duration from 2 weeks to 3 months, depending on the proposed use of the substance. Long-term testing in animals ranges in duration from a few weeks to several years. Some animal testing continues after human tests begin to learn whether long-term use of a drug may cause cancer or birth defects.

In-vitro (in the test tube) experiments, cell and tissue cultures can be used instead of using animals to test the product ingredients. The development of in-vitro methods based on biological materials (for example, skin or other human body cells) that will be suitable for reliably verifying the safety and compatibility of product ingredients. Development of High-throughput screening (HTS), Ultra HTS, automation, robotics and miniaturization techniques, made it feasible to screen 50,000 compounds a day with complex work stations. The development of in-silico methods (in the computer) is to determine the compatibility of substances on the basis of their chemical structure. Advantages of in-vitro tests are fast and cheap, human cells and tissues can be used, transgenic cells carrying human genes can be used, reduction of testing in animals, small amount of test material is required, lack of systemic effects, reduction of variability between experiments.

The classical way of pharmacological screening involves sequential testing of new chemical entities or extracts from biological material in isolated organs followed by tests in whole animals, mostly rats and mice but also higher animals if indicated. Most drugs in use nowadays in therapy have been found and evaluated with these methods.

Clinical pharmacology:

It is the scientific study of drugs in human. It includes pharmacokinetic and pharmacodynamic investigation in healthy volunteers and in patients. A clinical trial is a research study that tests a new medical treatment or a new way of using an existing treatment to see if it will be a better way to prevent and screen for diagnose or treatment of a disease. We define a clinical trial as a prospective study comparing the effect and value of intervention(s) against a control in human beings. It is only in the past several decades that the clinical trial has emerged as the preferred method in the evaluation of medical interventions.

Clinical trials for new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate trial. The drug‐development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases I, II and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV are post‐approval (Post marketing surveillance) studies. Now Phase 0 or micro dosing studies are performed to know the action of drug candidate in human being at early.

Table 1: Different phases of drug development.

Preclinical phases	In-vivo and in-vitro studies are carried out for pharmacokinetics, toxicity studies and formulating the drug.
Phase-I of clinical trial	Small scale trials in 20-80 numbers of healthy volunteers. Studied at single center for knowing the safety tolerability, pharmacokinetics and side effects.
Phase-II of clinical trial	Small scale trials in 100-300 numbers of patients as well as healthy   volunteers. Studied at single center to assess the efficacy and dosage. Long term toxicology studies are also carried out.
Phase-III of clinical trial	Large scale controlled trials in 800-3000 numbers of patients. Studied at multi-center for comparing the new drug with the existing drugs.
Phase-IV of clinical trial	Post marketing surveillance in patients for detecting any rare or long term ADRs.

After completion of preclinical studies successfully, the investigators files an ‘Investigational New Drug’ application (IND) to the government bodies [such as Central Drugs Standard Control Organization (CDSCO) in India] for allowance of initial testing in human beings. After the successful clinical trials and laboratory work, the investigators may file a New Drug Application (NDA). Permission to market a drug product will be given by the drug control authority after confirming the drug’s safety and effectiveness.

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