Pharmacological Drug Evaluation

 Preclinical research, the initial process of drug development, is intended to provide a preliminary assessment of the pharmacological activities, dose–response profiles, and toxicological potential of a drug. In addition to providing basic information about the pharmacology and safety of the test drug, preclinical studies determine the optimal formulation and dose for phase I clinical trials, identify potential toxic adverse effects, and provide the rationale for the proposed therapeutic indication. Approval to initiate human clinical trials is based largely on the results from preclinical pharmacological and toxicological studies. In many situations, agreements on criteria for proposed pharmacological outcomes and methods of toxicity testing are approached on a case-by-case basis. Regulatory authorities provide guidelines to outline general considerations for preclinical pharmacological studies. Studies on acute toxicity, subchronic and chronic toxicity, reproductive and developmental toxicity, mutagenicity, teratogenicity, and carcinogenicity should be well designed and performed.  The major tests performed on a drug candidate during preclinical stage include: 

• Pharmacodynamic studies

 • Pharmacokinetic studies 

• Bioequivalence and bioavailability

 • Acute toxicity 

• Chronic toxicity 

• Reproductive toxicity and teratogenicity 

• Mutagenicity or carcinogenicity

 • Immunotoxicity 

• Local toxicity and other tests

 Both the regulatory agency and the manufacturer must be satisfied that the testing conditions are common, acceptable procedures that achieve accurate and consistent experimental results. Pharmacology is the study of the activities of drugs and how they interact with the body. Pharmacodynamics (PD) examines more specifically how the drug exerts its pharmacological effects.  The study emphasizes how a drug interacts with cells or organs, drug effects and adverse reactions, and the characteristics of dose–response curves.  The information on the pharmacokinetics and pharmacodynamics of a drug in laboratory animals and humans is important for the design of toxicology studies as well as in evaluating safety and extrapolating toxicological data to humans. 

A pharmacokinetic (PK) study is conducted to establish the parameters for drug actions.  The processes that relate to the fate of a drug in the body involve absorption (A), distribution (D), metabolism (M), and excretion (E).  This study helps to identify any toxic effect and estimates the most appropriate method of drug administration and the optimum effective dosage for administration.

Generally,  ADME studies are conducted on two species, usually rats and dogs, at various dosage levels and in both male and female animals. Most of the time,  ADME studies are not performed for biopharmaceuticals. Proteins are catabolized by proteolytic enzymes into amino acid fragments and reutilized in the synthesis of endogenous proteins.  Their end-products of metabolism are not considered to be a safety issue.  This is in contrast to chemical drugs, which can form potentially toxic metabolites. After glomerular filtration, protein drugs are actively reabsorbed by the proximal tubules through endocytosis and then hydrolyzed within the cell to peptide fragments and amino acids and returned to the blood circulation; consequently, only small amounts of intact protein are detected in the urine.