Download Drug Discovery and Development Process and more Lecture notes Pharmacy in PDF only on Docsity!
TRANSCRIBED BY : JULIA MARIE BABAYEN-ON
M1: INTRODUCTION TO DRUG DISCOVERY AND
DEVELOPMENT
● Diseases and conditions that were once deemed incurable or fatal have been conquered with therapeutic agents designed to extend and improve quality of life. DISCOVERY OF ANTI-HIV DRUG ● Human immunodeficiency virus (HIV) ○ Causative agent of AIDS ● AZT (Retrovir®, azidothymidine) ○ First RT inhibitor approved for tx of AIDS ● Highly active antiretroviral therapy (HAART) ○ Multidrug cocktail treatment regimens CANCER DRUG DEVELOPMENT ● Survival rates for many types of cancer have dramatically improved as a result of the discovery and development of novel therapeutic agents. ● Overall cancer death rates in the United States have declined by 27% between 1991 and 2016 THE PROCESS ● A multidimensional one and as such requires the coordinated effort of individuals with a wide array of expertise A. The cost associated with the identification of useful and marketable therapeutic entities is staggering B. As of 2011, it is estimated that a single new drug costs over $1.75 Billion to discover and develop. ● Identification of a single marketed drug can require an initial examination of over 100,000 candidate compounds, hundreds of preclinical animal studies, and numerous clinical trials involving thousands of patients. ● Success rate: <0.001%
DRUG DISCOVERY
TARGET DISCOVERY
● The choice of a disease area and identification of a biological target LEAD DISCOVERY ● Structurally related compounds with the desired biological activity are identified (HIT and LEAD compounds) through biological screening of large numbers of compounds. LEAD OPTIMIZATION ● Lead compounds are modified and studied to identify potential candidates for drug development.
DRUG DEVELOPMENT
PRE-CLINICAL STUDIES
● Decides whether a drug is ready for clinical trials and involves extensive studies (e.g. animal models) that yield preliminary information on; ○ efficacy, ○ Toxicity ○ pharmacokinetic ○ safety SUBMISSION OF AN INVESTIGATIONAL NEW DRUG APPLICATION (INDA) ● INDA requests permission to move a clinical candidate into human study.
TRANSCRIBED BY : JULIA MARIE BABAYEN-ON
● INDA provides regulatory agencies with detailed preclinical data and detailed clinical protocols that describe how the compounds will be studied in human populations. CLINICAL TRIALS (PHASE I, II, AND III) ● PHASE I Safety and tolerability of an IND are examined in a small number of healthy individuals, typically 20 to 100 people. ● PHASE II - Safety and efficacy of IND are determined in around 100 to 300 patients. ● PHASE III - Efficacy of IND in larger population including comparison with standard therapies. SUBMISSION OF NEW DRUG APPLICATION (NDA) TO REGULATORY BODY ● NDA typically contains comprehensive details of both animal and human studies, ○ Safety findings ○ manufacturing procedures ○ dosing methods ○ storage conditions CLINICAL TRIAL (PHASE IV)/POSTMARKETING SURVEILLANCE (PMS ● PMS detects rare and long-term adverse effects across a much larger population of patients than could be supported in Phase III. ● Impact of PMS can include; ○ alterations to labeling based on safety results, ○ contraindication for use of the new drug in combination with other medications, or withdrawal of marketing approval if the findings are severe enough. ● Companies often use the data in PMS to identify competitive advantages, new markets, and new indications for the products.
ETHNOPHARMACOLOGY AND NATURAL PRODUCT
RESEARCH
● A glance at the pharmacopeia will show that many therapeutic agents, particularly anti infective and antineoplastic drugs, originate from natural products, rather than synthetic molecules. ● Examples: ○ Antibiotics - derived from fungal metabolites. ○ Paclitaxel - anticancer drug from yew tree ○ Vinca alkaloids - anticancer drugs produced by plants of the periwinkle family ○ Opiates - analgesic compounds from poppies ○ Artemether - antimalarial drug, semisynthetic derivative of artemisinin, produced by Chinese herb ● ADVANTAGES: ○ Such ready-made, highly evolved biomolecules stand a better chance of interacting with selected drug targets than do random synthetic molecules, and the pool from which they come is huge and largely untapped. ● DISADVANTAGES: ○ Accessibility due to geographical, cultural and political reasons ○ Continuing availability of the active compound may be uncertain. ○ Purification and structure determination of natural products is often difficult and time consuming "Exploiting such a ready-made compound library from natural products is seen as an attractive strategy for important therapeutic breakthroughs.
M2 : DRUG DISCOVERY AND DEVELOPMENT
PROCESS
TARGET IDENTIFICATION AND VALIDATION
● Drugs were mostly found by identifying API by: ○ Traditional medicines with folkloric use [ETHNOPHARMACOLOGY] ○ Serendipity ○ Classical methods in pharmacology ● Drug discovery and development involves ○ screening hit compounds, ○ medicinal chemistry, and ○ optimization of those target hits ■ For safety ■ efficacy ■ metabolic stability ■ and oral bioavailability Aims to identify the key molecular drivers of disease called TARGETS. TARGETS –naturally existing cellular or molecular structure involved in the pathophysiology of interest.
CLASSIFICATION
● Carbohydrates, lipids and PROTEINS ● “DRUG BANK” database most comprehensive databases of existing drug and targets RECEPTORS ● G-PROTEIN COUPLED RECEPTORS (GPCRs) ○ Most common; activate internal signal transduction pathways, and ultimately, cellular responses.
TRANSCRIBED BY : JULIA MARIE BABAYEN-ON
● The number of hits needs to be reduced, or filtered, to reach a more manageable figure. ● Pharmacodynamics ○ Activity in a biochemical assay is strictly a measure of how a molecule interacts with a target ● Pharmacokinetics ○ Most commercially successful drugs are administered orally, ○ Diffusion across Caco-2 (colon carcinoma) cell membranes (most common membrane permeability assay) ○ Ability for cytochrome P-450 enzymes to metabolize a hit is tested with liver microsome ● Final Concerns for Promotion of a Hit to a Lead ○ The surviving hits, sometimes called compounds of interest or similar, receive additional scrutiny. ○ Each remaining hit undergoes a handful of structural modifications.
SPECIAL CASES
SERENDIPITY
● Some scientific discoveries, including drugs, are labeled as serendipitous. ● Whether serendipitous drug discoveries are accidental is arguable, but the discoveries are unexpected. ● The sagacity required for such discoveries must be credited in part to the powers of observation of the researchers CLINICAL OBSERVATIONS ● Selective optimization of side activities (SOSA) ○ a drug with poor target specificity can be modified to enhance the side effect and decrease the original effect
LEAD OPTIMIZATION
● Aim: Identification of a compound which possesses the required properties (physicochemical, biological and pharmacological) of the targeted preclinical development candidate ● Focus: ADME parameter THE FRAMEWORK FOR SUCCESSFUL LEAD OPTIMIZATION
PRE-FORMULATION STUDIES
● Objectives: ○ To lay down FOUNDATION for developing a new drug entity into a pharmaceutical formulation ○ To provide STABILITY to the formulation OPTIMIZATION OF NEW DRUG ENTITY ● To improve stability and bioavailability through developing the molecule into: ○ Salt - Most widely used approach ○ Prodrug - Chemically modified inactive derivative of the active form DETERMINATION OF CHEMICAL PROPERTIES
- Partition coefficient - Drug’s ability to cross the phospholipid cell membrane
- Dissociation constant - Solubility in pH-dependent environment and extent of ionization
- Chirality - Ability of molecular entities to exist in different racemic forms
- Stability - Conditions in which the molecule is susceptible to degradation DETERMINATION OF PHYSICAL PROPERTIES
- Solubility - Most widely studied techniques during preformulation analysis
- Crystalline vs Amorphous form - Crystalline form is more stable but less water soluble
- Polymorphism - Ability of a compound to exist in different crystalline forms with different internal lattices
- Deliquescence and Hygroscopicity - Moisture level
- Particle size - Affects dissolution rate, solubility, bioavailability, content uniformity
- Particle shape - Affects surface area, flow properties, and compaction force
- Density - Dependent on particle size distribution and shape
- Flow property - Measured using Hausner’s ratio, Carr’s index, and angle of repose DRUG EXCIPIENT COMPATIBILITY
- Physical incompatibility a. No formation of new compounds; may involve organoleptic changes
- Chemical incompatibility a. Production of new unstable chemical entity
- Therapeutic incompatibility
TRANSCRIBED BY : JULIA MARIE BABAYEN-ON
a. aka: BIOPHARMACEUTICAL INTERACTION b. Associated with alteration in drug absorption
M3 : PRECLINICAL PHASE
PRECLINICAL TRIALS
● “Preclinical trials or nonclinical trials” ● Laboratory test of a new drug substance or medical devices, usually done on animal subjects ○ Determines a products’ ultimate safety profile ○ Develop adequate safety data before human trial ○ Part of INDA
TYPES OF TOXICITY TESTING
ACUTE TOXICITY TESTING
● Single high doses are given to small groups of animals ● Observed for mortality for 1-3 days ● Organ toxicity is examined by histopathology ● Lethal dose (LD50) ○ dose which kills 50% animals ○ Involves large numbers of animals, 14 days observation
REPEATED DOSE TOXICITY TESTING
● Carried out for a minimum of 28 days ● The test substance is administered regularly at a specific time SUB-CHRONIC ORAL TOXICITY TESTING ● The test substance is administered orally for 90 days. ● The test substance is administered regularly at a specific time. CHRONIC ORAL TOXICITY TESTING ● The test compound is administered over more than 90 days, and the animals are observed periodically. ● Provides inferences about the long-term effect of a test substance ● Essential for new drug entities NEUROTOXICITY STUDIES ● Studies the effects of a test substance on the CNS CARCINOGENICITY TESTING ● Observed for signs of toxicity and development of tumors. ● 18 months for mice and hamsters; 24 months for rats MUTAGENICITY TESTING ● Assess submicroscopic changes in the base sequence of DNA ○ Mutagenicity: permanent transmissible variations that can increase the frequency of mutations GENOTOXICITY TESTING ● Used to identify gene mutations, chromosome changes, and alterations in the DNA sequencing ○ Genotoxicity: ability of harmful substances to damage genetic information ONE-GENERATION REPRODUCTION TOXICITY TESTING ● Rodents are preferred (M and F) ● Observed for 1 spermatogenic cycle and 2 estrous cycles Animals are allowed to mate and parturition is observed. DEVELOPMENT TOXICITY/EMBRYOTOXICITY ● The compound is administered between the 8th and 14th day of pregnancy, and embryo lethal effects are observed. ● At the end of the study or on the 21st day of the study, a cesarean section is performed and parameters such as fetal deformation and mortality are observed. TOXICOKINETICS ● Deals with the kinetic patterns of higher doses of chemicals/toxins/xenobiotics
TRANSCRIBED BY : JULIA MARIE BABAYEN-ON
FACTORS TO CONSIDER WHEN USING IN VITRO
METHODS
● Know whether in vitro methods are accepted by regulatory authorities in your jurisdiction or not. ● Consider animal welfare issues. ● Know the limitations of in vitro methods
GUIDELINES FOR ETHICAL CONDUCT IN THE CARE
AND USE OF ANIMALS FOR PRECLINICAL TRIALS
IN DRUG TESTING
● Department of Agriculture’s (DA) Bureau of Animal Industry (BAI) ● Animal Welfare Act of 1998 (Republic Act No. 8485
ADMINISTRATIVE ORDER (AO) NO.
● The requirements for the authorization to conduct research using animals are the following:
- Description of the Animal Care and Use Program (ACUP) signed by a duly licensed veterinarian representing the entity,
- Animal Care and Use Program Accreditation Certificate issued by a duly recognized body or association,
- Animal Technician Training Program on Laboratory animal care and use, and
- Certification of Assurance that an Institutional Animal Care and Use Committee (IACUC) is in existence in the establishment. ETHICAL CONSIDERATION IN ANIMAL EXPERIMENTATION – 3R’S ● Replacement ● Reduction ● Refinement
