4 DEVELOPMENT OF NEW DRUG_230731_100643.pdf

PHARMACOLOGY PRINCIPLE: DEVELOPMENT OF A NEW DRUG DBB 20503 Basic Pharmacology Faculty of Health Sciences Universiti Sultan Zainal Abidin  MEDICINAL PLANTS Over the years, herbal and medicinal plants have been used in traditional medicine in treating sev...

PHARMACOLOGY PRINCIPLE: DEVELOPMENT OF A NEW DRUG DBB 20503 Basic Pharmacology Faculty of Health Sciences Universiti Sultan Zainal Abidin  MEDICINAL PLANTS Over the years, herbal and medicinal plants have been used in traditional medicine in treating several illnesses. Nature has become a diversity resource of medicinal plants for the past decades as large numbers of modern drugs today have been isolated from natural source. The isolations are mainly based on the agents used in traditional medicine. It is estimated that there are more than 35,000 plant species have been used in various human cultures worldwide for medical and health purposes  MEDICINE FROM PLANTS Digoxin Cardiac glycoside- inhibiting the Na+/K+- ATPase To treat congestive heart failure (CHF) and heart rhythm problem (atrial arrhythmias) Derived from foxglove -Digitalis sp (including D. lanata and D. purpurea MEDICINE FROM PLANTS Morphine-analgesic Alkaloid derived from an organic acid – extracted from opium poppy First isolated between 1803 and 1805  Morphine derivates MEDICINE FROM PLANTS Paclitaxel Extracted from yew trees (Taxus brevifolia) Discovered in 1960s 1983 – antitumour trials in humans 1993 – approved for medical use Ovarian cancer, breast cancer, lung cancer  MEDICINE FROM PLANTS Drug Chemical Indication Plant Aspirin Salycylate Analgesic White willow tree Caffeine Xanthine Mental alertness Camellia sinensis Cocaine Alkaloid Anesthetic Coca leaves Codeine Alkaloid Analgesic Opium poppy Digoxin Steroid Heart muscle Purple foxglove Ipecac Alkaloid Vomiting Psychotria ipecacacuanha Pseudoephedrine Alkaloid Nasal congestion Ephedra sinica Quinine Alkaloid Malaria Cinchona pubescens Paclitaxel Terpenoid Lung cancer Yew tree  MEDICINE FROM BIOLOGICAL SOURCES Substance Use Blood products – e.g. Coagulation factors Blood disorders e.g. Haemophilia Vaccines Vaccination Antibodies Passive immunization Insulin Diabetes Antibiotics Infections  MEDICINE FROM BIOLOGICAL SOURCES Penicillin (discovered by Alexander Fleming) 1928 – discovered, a mould responsible for cell death 1939 – isolation and purification  MICROBIOLOGY AND MEDICINES IVERMECTIN (1981) – an antiparasitic drug isolated from a soil fungus LOVASTATIN (1982) – a cholesterol synthesis inhibitor isolated from an Aspergillus species TACROLIMUS (1987) – immunosuppressant isolated from a Streptomyces species  DRUG DEVELOPMENT Bringing one new drug to the public typically costs a pharmaceutical or biotechnology company on average more than $1 billion and takes an average of 10 to 15 years How to Identify the Target? Target: the naturally existing cellular or molecular structure involved in the disease that the drug-in-development is meant to act on So: you need to: Understand the molecular mechanism of the disease of interest Identify a therapeutic target in this mechanism (enzyme, gene, receptor, channel, etc) Comes out of basic research  DRUG DEVELOPMENT PROCESS 1. Discovery and development 2. Preclinical research 3. Clinical research 4. FDA review 5. FDA Post-market safety monitoring  DRUG DISCOVERY a process which aims at identifying a compound therapeutically useful in curing and treating disease. involves the identification of candidates, synthesis, characterization, validation, optimization, screening and assays for therapeutic efficacy. Once a compound has shown its significance in these investigations, it will initiate the process of drug development earlier to clinical trials. New drug development process must continue through several stages in order to make a medicine that is safe, effective, and has approved all regulatory requirements  1. Discovery and Development Researchers discover new drugs through: New insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease Tests of molecular compounds to find possible beneficial effects against any of a large number of diseases Existing treatment that have unanticipated/side effects New technologies, such as those that provide new ways to target medical products to specific sites within the body or to manipulate genetic material Disease Process Identification of cellular and genetic factors that play a role in specific diseases Then, search for chemical and biological substances that target these biological markers and are likely to have drug-like effects  depression normal Example 2: Breast cancer Studying the biology of cancer cells Comparing the genetics found in DNA and cellular processes of cancer cells to healthy cells to identify important steps in the cancer growth process that a drug could possibly fix About 20% of all breast cancers have an abnormal amount of a certain protein. It is called HER2 and controls the growth and spread of cancer cells Four drugs were created to target HER2: trastuzumab (Herceptin), lapatinib (Tykerb), pertuzumab (Perjeta), and ado- trastuzumab emstansine (Kadcyla). Other mechanism: apoptosis pathway Unwanted effects of existing treatment CISPLATIN Side effect Cisplatin treatment causes nephrotoxicity, hepatotoxicity and cardiotoxicity to the patients (Dasari & Bernard 2014). Resistances -despite effective, it develop cell resistance New Technologies Computational drug discovery Understanding the chemical structure of a drug target Scientists may use computers to mimic how a potential drug interacts with its target Using details from computer models, researchers can then design chemical compounds that interact with the specific drug target Nanotechnology a drug can be accurately delivered to the targeted region in the body. This can help treat cancer patients with a customized treatment plan. Combinatorial Chemistry – new molecules Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even million) of compounds in a single process using computer software. In a traditional organic synthesis lab, the chemist does the standard reaction A + B --> C. But with combinatorial chemistry A is a mixture of perhaps 5 components and B is a mixture of 10 so instead of getting one product the chemist now gets 50. The basic principle of combinatorial chemistry is to prepare libraries of very large number of compounds then identify the useful components of the libraries Targeted Therapy They work by targeting specific genes, proteins or enzymes For example, in cancer, these gene and proteins are found in cancer cells or in cells related to cancer growth, like blood vessel cells Targeted drug delivery using liposomes, polymeric micelles, nanostructures, etc 1. Discovery and Development New compounds are isolated and purified from natural sources or synthesised In-vitro assays are developed to measure the effect of potential therapeutics Thousands of compound may be potential candidates for development as a medical treatment These compounds are tested for biological activity After early testing, only a small number of compounds look promising and call for further study.  COMPOUNDS FROM NATURAL SOURCES phytochemical compounds derived from natural plants have attracted greater interest among researchers due to their beneficial effects towards human health, safety and cost effective (Bacanli et al. 2017). widely distributed in plant derived fruits, beverages and herbal remedies. more than 10000 phytochemicals have been identified, many are yet remains unknown and need to be explored 1. Discovery and Development Once researchers identify a promising compound for development, they conduct experiments to gather information on: Pharmacokinetics: ADME Pharmacodynamics: potential benefits and mechanisms of action The best dosage Administration: the best way to give the drug (such as by mouth or injection) Side effects or adverse events (toxicity) How it affects different groups of people (such as by gender, race, or ethnicity) differently How it interacts with other drugs and treatments Its effectiveness as compared with similar drugs 1. Discovery and Development Promising compounds may be chemically modified to improve target specificity, potency, chemical and metabolic stability, water solubility, and other pharmacological parameters 2. Preclinical Research Safety and efficacy testing in laboratory animals (e.g. mice, rats) Before testing a drug in people, researchers must find out whether it has the potential to cause serious harm, also called toxicity. 2. Preclinical Research Usually, preclinical studies are not very large These studies must provide detailed information on dosing and toxicity levels Several quantities estimates are desired no effect dose- max dose at which specified toxic effect is not seen minimum lethal dose- the smallest dose that killed any experimental animal Median lethal dose (LD50)- the dose that killed 50% of animals After preclinical testing, researchers review their findings and decide whether the drug should be tested in people The Investigational New Drug Process Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to Food and Drug Administration (FDA) before beginning clinical research In the IND application, developers must include: Animal study data and toxicity (side effects that cause great harm) data Manufacturing information Clinical protocols (study plans) for studies to be conducted Data from any prior human research Information about the investigator Approval The FDA review team has 30 days to review the original IND submission Must be reviewed and approved by the FDA The process protects volunteers who participate in clinical trials from unreasonable and significant risk in clinical trials 3. Clinical Research Studies, or trials, that are done in people Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies Phase 1 aims at testing drug safety and dosage on 20 to 100 volunteers. Phase 2 studies efficacy and side effects, engaging several hundreds of people with the disease. Phase 3 is the longest one, with up to 3,000 people involved. No more than 10% of molecules entering the clinical trial stage survive through all three phases and get approved by FDA Designing Clinical Trials Who qualifies to participate (selection criteria) inclusion/ exclusion How many people will be part of the study How long the study will last Whether there will be a control group and other ways to limit research bias How the drug will be given to patients and at what dosage What assessments will be conducted, when, and what data will be collected Clinical Research Phase Studies Phase 1 Study Participant: 20 to 100 healthy volunteers or people with the disease/condition. Length of Study: Several months Purpose: Safety and dosage, to find the max tolerated dose, to prevent severe toxicity Approximately 70% of drugs move to the next phase Phase 1 Increasing, by stages, the administered dose to determine those which are tolerated without adverse effect The dose initially tested is determined according to the results of the animal experimentation, by taking a sufficient safety factor to avoid any serious risk It is not however licit to give drugs having an important toxicity, such as the anticancer drugs, to healthy volunteers; these drugs are tested in patients with the disease Blood and urine sampling is made during this phase 1 to obtain the first pharmacokinetic data Phase 2 Study Participants: Up to several hundred people with the disease/condition (100-500) Length of Study: Several months to 2 years Purpose: Efficacy and side effects Approximately 33% of drugs move to the next phase Phase 2 The goal of this phase is to check the therapeutic activity expected from the data of the animal experimentation, and to determine the effective dosage This study can be carried out comparatively to a placebo (inactive drug) or a reference drug, for example the efficacy of a new analgesic could be compared with that of paracetamol/acetaminophen  PLACEBO EFFECT Placebo refers to the inactive substance itself, while the term placebo effect refers to any effects of taking a medicine (placebo) that cannot be attributed to the treatment itself. In medical research, some people in a study may be given a placebo, while others get the new treatment being tested. The purpose of doing this is to determine the effectiveness of the new treatment. If participants taking the actual drug demonstrate a significant improvement over those taking the placebo, the study can help support the claim for the drug's effectiveness. Phase 3 Study Participants: 300 to 3,000 volunteers who have the disease or condition Length of Study: 1 to 4 years Purpose: Efficacy and monitoring of adverse reactions Approximately 25-30% of drugs move to the next phase Phase 3 The aim of this phase is to specify the therapeutic efficacy of the product, at determined dosages, comparatively to a placebo or a reference drug to assess the importance of adverse effects Can be difficult to design and execute and are expensive –large participants involved and masses of data The drug formulated is intended for the market If phase 3 meets expectations, application is made for permission to market the new agent- from FDA  4. FDA Drug Review If a drug developer has evidence from its early tests and preclinical and clinical research that a drug is safe and effective for its intended use, the company can file an application to market the drug The FDA review team thoroughly examines all submitted data on the drug and makes a decision to approve or not to approve it New Drug Application A New Drug Application (NDA) tells the full story of a drug Its purpose is to demonstrate that a drug is safe and effective for its intended use in the population studied FDA review teams examine all of the data collected from the start of preclinical research through completed clinical trials and make a decision to approve or not to approve the drug for a purposed population, depending on the benefits and risks of the therapy FDA Approval FDA determines that a drug has been shown to be safe and effective for its intended use - APPROVED Phase 4 (Post marketing monitoring) Study Participants: Several thousand volunteers who have the disease/condition Purpose: Safety and efficacy The drug which received its New Drug Approval, is marketed by the pharmaceutical industry, prescribed by the doctors and dispensed by the pharmacists Monitoring the safety of drug under actual conditions of use in large numbers of patients 5. FDA Post-Market Drug Safety Monitoring Phase IV is necessary to better determine the therapeutic efficacy and the tolerance of drug under the usual conditions of use in patients different by their age, their various diseases and the other drugs used concomitantly The true picture of a product’s safety actually evolves over the months and even years that make up a product’s lifetime in the marketplace Some rare adverse effects are detected only during this phase or only after a few years of use FDA reviews reports of problems with prescription and over-the- counter drugs, and can decide to add cautions to the dosage or usage information, as well as other measures for more serious issues INDs for Marketed Drugs If sponsors want to further develop an approved drug for a new use, dosage strength, new form, or different from (such as an injectable or oral liquid, as opposed to tablet form), OR If they want to conduct other clinical research or a post-market safety study Generic Drugs New drugs are patent protected when they are approved for marketing. This means that only the sponsor has the right to market the drug exclusively Once the patent expires, other drug manufacturers can develop the drug, which will be known as a generic version of the drug. May file an abbreviated new drug application (ANDA). Generic drugs are comparable to brand name drugs and must have the same Dosage form Strength Safety Quality Performance characteristics Intended use SUMMARY THE END Thank You……