a SS — 1; DRUG DEVELOPMENT, PROGESS INTRODUCTION: « Drugs are perhaps the most important therapeutic interventions in modern healthcare. * Development of new drugs is always a prime concern for research based pharmaceutical industries. «Many drug discoveries in the past were empirical, i.e., they were based on observations of certain phenomena. + The observations by William withering (1741 to 1799) that a decoction of foxglove treated dropsy, i.e., congestive cardiac failure (CCF) was one such discovery. DEFINITION: “Drug development process is defined as a series of well defined steps, for drugs of new, safe and effective treatment to increase health and quality of life” Steps involved in drug discovery: DRUG DISCOVERY TARGET SELECTION LEAD IDENTIFICATION LEAD OPTIMIZATION PRODUCT DEVELOPMENT i - Scanned with CamScanner1. Target selection: Before discovery of drug J Disease to be treated needs to be understood, to identify the "underlying cause of the same” J Study of disease mechanism J Helps improper research t Helps to formulate a possible tip to slow/reverse the disease progress Target for therapeutic interventions include: * Receptors * Proteins « Enzymes * DNA * RNA * Ribosomal targets Methods used for target identification include: Cellular biology (a) Classical methods Ss Mecca biology Genomics (b) Newermethods Pa Proteomics Target validation: In target validation, demonstration is required to prove that: {a) Identified molecule target is involved in disease process. Scanned with CamScanner(b) Binding of drug to the target produces curative effect. Process involved in validation: In Vitro phase In vivo face Result Defines clinical potential of target © It's also important to determine “druggability of target” © Druggability of target is defined as the ability of a target to bind to a drug. 2, Lead identification: In lead identification process L Compounds that interact with the target protein is identified Sources of compounds include: {a) Natural products from microbes, plants (or) animals. (b) Compound libraries: 1° screening J Identifies Hits from compound libraries t Hits are retested t Retest is done independently of 1* assay (or) on a different day Scanned with CamScanner_———————— Compound t Exhibits some activity within a statistically significant range y It is termed as “confirmed Hit” 1 Proceeds to dose response screening 3. Lead optimization: In lead optimization process t The chemical structure of a confirmed hit is defined { Helps to improve drug characteristics L Helps to produce preclinical drug candidate Different parts of lead optimization include: a) Kinetic studies b) Dynamic studies ¢) Absorption studies d) Distribution studies €) Metabolism studies f) Excretion studies Then the final drug product was developed. Then the final product was developed. Scanned with CamScannerVARIOUS APPROACHES TO DRUG DISCOVERY emetic Reeth Reena nk eno Co Bn cc Can Preclinical testing/evaluation: (a) Selectivity testing: The primary aim of preclinical testing is to obtain basic information on the drug effects that may be used to predict safe and effective use in humans. There are species difference between humans and animals. Hence drugs needed testing in humans before marketing. Preclinical testing can be divided into two broad categories. They are: 1, Pharmacological testing 2. Toxicological testing [ARMACOLOGICAL TESTING These tests are to determine whether the substance has effectiveness and a reasonable safety profile. Components of pharmacological testing/evaluation include: (a) Selectivity testing (b) Pharmacological profiling (c) Testing in animal models of disease (d)Safety pharmacology It involves two stages: (i Screening of selectivity Scanned with CamScannerne (i) Binding assays (i) Screening of selectivity: The selectivity of a compound for a chosen molecular target needs to be assessed, because it determines the potency of the drugs. (ii) Binding assays: Binding assays needed to determine the dissociation constant of the test component as a measure of affinity to the receptor. (b) Pharmacological profiling: Pharmacological profiling refers to determining the pharmaco-dynamic effects of a new compound. Pharmacological profiling may be as: (i) Invitro models {ii) Invivo models (i) Invitro models:- « It involves the studies on isolated tissues. « In vitro profiling is applicable to studies on smooth muscles, cardiac muscles, brain slices. « Mostly tissue is obtained from a freshly killed (or) anaesthetized animal and suspended in warmed oxygenated physiological fluids solution. ii) Invivo models: + Itinvolves testing on normal animal models. « These invivo profiling are time consuming and very expensive. (c) Testing in animal models of disease: Animal models of disease can be divided into three models: 1) Acute physiological and pharmacological models. 2) Chronic physiological and pharmacological models. 3) Genetic models, Scanned with CamScanner1) Acute physiological and pharmacological models: * These models are intended to mimic certain aspects of clinical disorder. Example: Hot plate for analgesic drugs as a model of pain. + Flectrical stimulation of brain to induce seizures as a model of epilepsy. 2) Chronic physiological and pharmacological models: These models involve the use of drugs (or) physical interventions to induce an ongoing abnormality similar to clinical condition. Example: self administration of opiates, nicotinic drugs as a model of drug dependence. 3) Genetic models: « These are transgenic animals provided by (or) over expression of specific genes deletion, to show abnormalities, resembling the human disease. « The development of transgenic technology has allowed inbred stains to be produced with the gene abnormality to be present throughout the animal life. (d) Safety pharmacology: « Safety pharmacology is the evaluation and safety of potentially life threatening pharmacological effects of a potential drug which is unrelated to the desired therapeutic effect and may present a hazard. * Safety pharmacology seeks to identify unanticipated effects of new drugs on major organ functions. « To detect possible, undesirable, (or) dangerous effects of exposure of their drug in the therapeutic doses. Pharmacological evaluation/testing/screening involves three levels of study: 1) Molecular level studies 2) Cellular level study 3) Whole animals 1) Molecular level study: * In this, drug is studied for its selectivity for various receptors and its activity against selective enzyme systems. * Cell membrane fractions from organs (or) glands etc. are used. 2) Cellular level study: Scanned with CamScanner« By using cell and tissue culture & computer programs, the pharmacological action, is assessed to stimulate human and animal system. « Isolated tissues like blood vessels, heart, lungs, ileum of rat (or) guinea pig are used. 3) Whole animal study: « This is to determine the effect of drugs (or) substances on organ systems and disease models. « Example: Study of anti-hypertensive effects in hypertensive rats. * Pharmacological testing ensures that the drug does not produce any potential hazardness (or) serious unwanted effects. TOXICOLOGICAL TESTING/EVALUATION| « All drugs are toxic at some dose i.e. no drug is safe at all doses. Toxicity data on animals cannot be completely extrapolated to humans because of reason like species, variation, etc. But it is necessary to test the drug first in several species of animals. « Toxicity studies are undertaken to determine the test drugs potential for toxicity with short term, long term use etc. * Test drugs are studied at various dose levels to determine effects, potency and toxicity. Toxicity studies Various toxicity studies are recommended by regulatory authorities, as follows: a) Acute toxicity studies b) Sub acute toxicity studies, ©) Chronic toxicity studies d) Reproduction studies e) Carcinogenic studies f) Geno-toxicity studies Scanned with CamScanneree {a) Acute short term toxicity studies: + In this one drug (or) substance is administered at various dose levels to find the largest single dose that will not produce a toxic effect. + In this test animals are compared with control for eating and drinking habits, weight change, toxic effects and any untoward effects, usually over a 30 days post dosing period. + Biological samples are tested to detect changes in clinical chemistry, and any other changes that could indicate toxicity. (b) Sub acute toxicity studies: + In this drug (or) substance is given daily for a minimum period of two weeks at three (or) more dosage levels to two animal species. + The study is useful in generating evidence to support the initial administration of a single dose and human clinical testing. * Generally, 1/10th of the highest non-toxic dose in mg per kg(mg/kg) bodyweight is the initial dose in human. {c) Chronic toxicity studies: « In this, animal studies of three to six months are required. If the tested drug (or) substance is intended to be given for one week (or) more in humans. * For chronic illness, animal studies for one year (or) longer is required. « The comparative data of test & control during sub-chronic and chronic studies are to be generated. Ex: body weight, hematology, clinical chemistry, urine analysis etc. (d) Reproduction studies: « In this, drug/substance effects in reproductive performance and studies in mammalian species to assess fe: ity and mating behavior. « The maternal parents, fetus, neonates, and wearing offspring are evaluated for anatomic abnormalities, growth and development. Scanned with CamScanner(e) Carcinogenicity studi « These studies are usually carried out ina limited number of rats and mouse strains for which there is reasonable information on spontaneous tumor incidence, » Dose used for the studies should be minimum tolerated dose to elicit signs of minimal toxicity without significantly altering the animal’s normal life by effects, other than carcinogenicity. « In this survivor animals are killed, and studied at different time & data on causes of death, tumor incidence, type and sight, and findings of necropsy. (f) Genotoxicity (Mutagenicity) studies: « These studies are performed to determine the effects of drug on genetic stability and mutations in bacteria (or) mammalian cells in culture, dominant lethal tests. * Apart from the above toxicological studies, some quantitative estimates are desirable. + Some invitro methods are used, because to avoid excess animal in animal studies, but the predictive value in-vitro methods are limited. NPC erels * Investigational new drug (IND) application is defined as the petition, through which a drug sponsor requests the FDA to allow human testing of its drug product * INDA is required to be submitted to drug regulatory authority before initiation of clinical trial. * The INDA can be submitted by the sponsor, but may employ CRO to conduct the actual studies. « IND application provides the FDA with the data necessary to decide whether the new drug and the proposed clinical trials pose a reasonable risk to the human subjects participating in the study. Scanned with CamScanner——————————— INDICATIONS + INDA is needed, when you want to conduct a clinical trial of an unapproved drug. * Itis needed when any drug, the composition of which is not generally recognized as safe and effective for use under the conditions prescribed, recommended (or) suggested in the labeling. Types of IND: There are four types of IND, they are: 1. Investigational INDs 2. Commercial INDs 3. Emergency use INDs 4. Treatment IND 1) Investigator INDs: These are submitted by physician, who both initiates and conducts an investigation and under whose immediate direction, the Investigation drug is administered (or) dispensed. 2) Commercial INDs: There are submitted by companies to obtain marketing approval for a new product. 3) Emergency use IND: This IND allows the FDA to authorize use of an experimental drug in an emergency situation. 4) Treatment IND: It is submitted for experimental drugs, showing promise in clinical testing of serious (or) immediately life threatening conditions. Scanned with CamScannerData to be submitted along with application to conduct clinical trials: Data to be submitted along with application to conduct clinical trial of new drugs for marketing are as follows: 1) Animal pharmacology and toxicology studies 2) Manufacturing information 3) Clinical protocols and investigator information 1) Animal pharmacology and toxicology studies: Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans 2) Manufacturing information: Includes composition, manufacturer, stability and controls, used for manufacturing the drug substance and the drug product. 3) Clinical protocols and investigators information: * Detailed protocols and clinical studies to assess whether the initial phase trials will be exposed subjects to unnecessary risks. «Investigators information contains administration of experimental compound to assess whether they qualified clinical trials. Format & content of IND: A. Cover sheet (from FDA-1571) a) Name, address, telephone number of sponsor b) Identification of phases ¢) Commitment not to begin clinical trials and till IND approval d) Commitment by IRB form-56 ) Commitment for conducting clinical trials f) Name, title - monitor g) Name, tlle - person h) Name, Address of CRO i) Signature of sponsor B. Table of Contents C. Investigators brochure D. Study protocol E, Investigator facilities and IRB data Scanned with CamScannerF, Chemistry, manufacturing and control data G. Previous human experience. Outcomes from IND: * 30 days after an IND is submitted to the FDA, if the sponsor has not heard anything from the FDA, it can be assumed that the drug is not on a clinical hold and clinical trials may be started. « Investigator brochure will be used during that important first clinical study and in every clinical study acts as the approved labeling for the drug, while it is under an IND. IDRUG CHARACTERIZATION) Drug characterization involves finding of biological and physio-chemical properties of potential drug molecules. ‘> Biological characteriz: Interaction of drug molecules with biological systems. Ex: Receptor binding, Enzyme inhibition. Physio-chemical characterization: Physical and chemical characterization of potential drugs. Ex: Solubility, Pka X- ray, NMR, IR, UV-visible, MS, PET. mn; BIOLOGICAL CHARACTERIZATION It is needed to assess whether the molecule will likely to work in humans. Goals: 1. To find efficacy 2. Assess toxic effects Further divided into: (a) Biochemical assay (b) Cellular assay (c) System/whole animal assay. (a) Bio-chemical assay: Scanned with CamScanner+ Mechanism of action at molecular level. « Receptor binding assays (affinity and selectivity) * Metabolic processing. (b) Cellular Assay: «Cellular cultures: cell penetration, receptor, activity, transport. + Isolated tissues: effects on specific tissues, possible toxicity. « Liver tissues: Drug metabolism, Drug interaction. (c) System/whole animal assay: « Rat, mouse: Toxicity, LD50, organ-specific efficacy. + Dog, rabbit, Guinea pig, monkey: Pharmacokinetic/Pharmacodynamic, bioavailability, toxicity. « Lab animal models for disease: efficacy and toxicity. PHYSIO-CHEMICAL CHARACTERIZATION Physical and chemical properties of a drug are critical for knowing how it can be formulated (or) stored, (or) administered. Solubility Pka Partition coefficient: octanol : water Stability Chemical structure: Mass spectroscopy, NMR, X-ray, crystallography. Impurities: TLC, HPLC, GC, Mass spectroscopy. Polymorphism IDOSAGE FORM] At some stage, a decision needs to be made about the dosage form(s) for the delivery of the drug (Ex: tablet (or) capsule, (or) induction). The factors that determine which dosage forms are to be used are many & involved marketing considerations apart from scientific considerations. Scanned with CamScannerDosage form Comments 1. Tablet & capsule ‘Convenient & commonest dosage forms But likely tobe no good, if drug can't be absorbed in GI tract (or) if patient can’t swallow them. 2. Injection & infusions Rapid action Impractical for treating chronic illness 3, Pessaried & Suppositories 4. Solutions, suspensions & elixirs Can deliver the drug to local area, where required Havelimited general use. Useful for children & elderly Burare bulky & less useful, if drugis unpalatable (or) unstable in the presence of water. 5._Ointments, creams & paints ‘Uses restricted to topical application. 6. Aerosols & drug powderinkalations 7. Trans-dermal patches Good for drugs required in the lungs Difficult to administer dose comectly Convenient, if the doseneeds tobe released over a long period Causeinitation Therapeutic considerations play an important role in deciding the dosage form to formulate. Example: Even tablet that absorbs in alimentary tract (i.e. intestine) is unsatisfactory, if that drug is destroyed by stomach acids. Tablet is not suitable, if it can’t absorb in alimentary tract. Instead of tablet, an injection is suggested as an alternative. Scanned with CamScanner