Drug Discovery and Development PDF

Okay, here is the converted markdown format of the provided images or documents: ### Drug discovery process **Drug:** A chemical substance of known structure, other than a nutrient or an essential dietary ingredient which, when administered to a living organism, produces a biological effect. **Di...

Okay, here is the converted markdown format of the provided images or documents: ### Drug discovery process **Drug:** A chemical substance of known structure, other than a nutrient or an essential dietary ingredient which, when administered to a living organism, produces a biological effect. **Discovery phase:** Identification of a new chemical entity as a potential therapeutic agent. **Development phase:** Compound is tested for safety and efficacy for one or more clinical indications, and in suitable formulations and dosage form. **Drug Discovery:** Candidate molecules are chosen on the basis of their pharmacological properties. * **Preclinical development:** Non-human studies (e.g. toxicity testing, pharmacokinetic analysis and formulation) are performed. * **Clinical development:** The selected compound is tested for efficacy, side effects and potential dangers in volunteers and patients. **Drug Discovery:** Drug discovery is a multifaceted process, which involves identification of a drug chemical therapeutically useful in treating and management of a disease condition. Typically, researchers find out new drugs through new visions into a disease process that permit investigator to design a medicine to stopover or contrary the effects of the disease. The process of drug discovery includes the identification of drug candidates, synthesis, characterization, screening, and assays for therapeutic efficacy. When a molecule avails its satisfactory results in these investigations, it will commence the process of drug development subsequent to clinical trials. Drug discovery and development is an expensive process due to the high budgets of R&D and clinical trials. It takes almost 12-15 years to develop a single new drug molecule from the time it is discovered when it is available in market for treating patients. | Drug Discovery | Pre- clinical | Clinical trials | Regulatory approval | | :-------------------- | :------------------------------------- | :---------------------- | :------------------ | | 5,000-10,000 compounds | 250 compounds | 5 compounds | 1 new drug | | Target identification | In vitro and in vivo toxicity ADMETPK/PD | Phase I, Phase II, Phase III | | | Assay development | | | | | Lead generation | | | | | 3-5 years | 1-2 years | 6-7 years | 1-2 years | **Stages of drug discovery and development include:** * Target identification * Target validation * Lead identification * Lead optimization * Product characterization * Formulation and development * Preclinical research * Investigational New Drug * Clinical trials * New Drug Application * Approval ### The Drug Discovery Process This image displays a diagram of the drug discovery process, with timelines, costs and failure rates at each step: * Early Discovery 2-5 years - $4M * Development: 5-10 years - $40M * Licensing: 1-2 years - $2M+ The key stages and what happens in each is shown as follows: * Target ID/Target Validation/Target selection * Lead/Lead Candidate * Preclinical Development * Phase I (FTIH) First Time in Humans *Phase II(POC) Proof Of Concept * Phase III Multicenter Trials * Phase IV Post Marketing Surveillance. What actions take place at each stage and the attrition ("failure") rate is shown. It also includes some other important notes about the phases like, **Each stage output is the input of the next one**, **how the system works and provides back ups**, **what individual pipelines represent and under what conditions stages fail**. **Target Identification** The first step in the discovery of a drug is identification of the biological origin of a disease, and the potential targets for intervention. Target identification starts with isolating the function of a possible therapeutic target (gene/nucleic acid/protein) and its role in the disease. Identification of the target is followed by characterization of the molecular mechanisms addressed by the target. An ideal target should be efficacious, safe, meet clinical and commercial requirements and be druggable. The techniques used for target identification may be based on principles of molecular biology, biochemistry, genetics, biophysics, or other disciplines. **Various targets of drug action**. The majority of drug targets are: a) G-protein coupled receptors b) Nuclear receptors c) Ion channels d) Enzymes **Target Validation** Target validation is the process by which the expected molecular target-for example gene, protein or nucleic acid of a small molecule is certified. Target validation includes: determining activity, the structure of molecular interacting (SAR) drug-resistant mutant to the mall presunmedtarget. Target validation is the process of demonstrating the functional role of the identified target in the disease phenotype. **Target Identification Strategies** * Genomics * Proteomics * Metabolic pathways analysis: Molecular Biology **Lead Identification** A chemical lead is defined as a synthetically stable, feasible, and druglike molecule active in primary and secondary assays with acceptable specificity, affinity and selectivity for the target receptor. This requires definition structure activity relationship as well as synthetic determination in vivo efficacy and preliminary engagement. **Characteristics of a chemical lead are:** * Drug ability (preliminary toxicity) * Synthetic feasibility * Select assays * vitro assessment of drug resistance and efficacy potential * Evidence of in vivo efficacy of chemical class * PK/Toxicity of chemical class known based on preliminary toxicity or in silico studies. **Lead optimization** Lead optimization is the process by which a drug candidate is designed after an initial lead compound is identified. The process involves synthesis and characterization of a potential drug to build up a representation of in what way chemical structure and activity are related in terms of interactions with its targets and its metabolism. The purpose of lead optimization is to maintain favorable properties in lead compounds, while improving on deficiencies in lead structure. **Product Characterization** When any new drug molecule shows a promising therapeutic activity, then the molecule is characterized by its size, shape, strength, weakness, use, toxicity, and biological activity. Early stages of pharmacological studies are helpful to characterize the mechanism of action of the compound. **Formulation and Development** Pharmaceutical formulation is a stage of drug development, during which the physicochemical (chemical) properties are characterized characterized so that bioavailability and optimal dosing is done or a specific administration route. During preformulation studies the following parameters are evaluated: * Solubility in different media and solvents * Dissolution of the active pharmaceutical ingredient (API) * Solid-state properties (polymorphs, particle size, particle shape etc.) * Formulation development of new chemical entities (NCE) * Optimization of existing formulations * Process development for selected dosage forms * Novel formulations for improved delivery of existing dosage forms **Preclinical Testing** Pre-clinical research in drug development process involves evaluation of drug's safety and efficacy in animal species that conclude to prospective human outcome. The pre-clinical trials also have to acquire approval by corresponding regulatory authorities. The regulatory authorities must ensure that trials are conducted in safe and ethical way and would give approval for only those drugs which confirm to be safe and effective. The pre-clinical trials can be conducted in two ways: General pharmacology and Toxicology. Pharmacology deals with the pharmacokinetic and pharmacodynamic parameters of drug. Pharmacokinetic studies are very important to make known the safety and efficacy parameters in terms of absorption, distribution, metabolism and excretion. **Clinical Research** Clinical trials are conducted in people (volunteer) and intended to answer specific questions about the safety and efficacy of drugs, vaccines, other therapies, or new methods of using current treatments. Clinical trials follow a specific study protocol that is designed by the researcher or investigator or manufacturer. Before a clinical trial begins, researchers review prior information about the drug to develop research questions andobjectives. **Then, they decide:** * Selection criteria for participants * Number of people take part of the study * Duration of study * Dose and route of administration of dosage form * Assessment of parameters * Data collection and analysis **Phase 0 clinical trial** Phase 0 implicates investigative, first-in-human (FIH) trials that are conducted according to FDA guidelines. Phase 0 trials have single sub-therapeutic doses given to 10 to 15 volunteers and give pharmacokinetic data or help with imaging specific targets without exert pharmacological actions. Pharmaceutical industries perform Phase 0 studies to pick which of their drug applicants has the preeminent pharmacokinetic parameters in humans. **Phase 1: Safety and dosage** Phase I trials are the first tests of a drug with a lesser number of healthy human volunteers. In most cases, 20 to 80 healthy volunteers with the disease/condition participate in Phase 1. If a new drug is proposed for use in diabetes patients, researchers conduct Phase 1 trials in patients with that type of diabetes. Phase 1 studies are closely monitored and collect information about Pharmacodynamics in the human body. **Phase 2: Efficacy and side effects** Phase II trials are conducted on larger groups of patients (few hundreds) and are aimed to evaluate the efficacy of the drug. These trials are not sufficient to confirm whether the drug will be therapeutic. Phase 2 studies provide with additional safety data to the researchers. Researchers use these data to refine research questions, develop research methods, and design new Phase 3 research protocols. Around 33% of drugs travel to the next phase. Most prominently, Phase II clinical studies aid to found therapeutic doses for the large-scale Phase. **Phase 3: Efficacy and adverse drug reactions monitoring** Researchers plan Phase 3 studies to prove whether a product deals an action benefit to a specific people or not. These studies comprise 300 to ,000 volunteers. Phase 3 studies deliver most of the safety data. The previous study might not able to detect less common side effects. But phase 3 studies are conducted on large no. of volunteers and longer in duration, the results are more probable to detect long-term or uncommon side effects. **Phase 4: Post-Market Drug Safety Monitoring** Phase 4 trials are conducted when the drug or device has been approved by FDA. These trials are also recognized as postmarketing surveillance involving pharmacovigilance and continuing technical support after approval. There are numerous observational strategies and assessment patterns used in Phase 4 trials to evaluate the efficacy, cost effectiveness, and safety of an involvement in real-world settings. I hope this is helpful! Let me know if you have any other questions.