Drug Development PDF

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Drug development Discovery and development YFRM202 2  Lecture Overview In this lecture you can expect to learn about the process of drug deve...

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Drug development Discovery and development YFRM202 2  Lecture Overview In this lecture you can expect to learn about the process of drug development. You have previously learned about adverse event reporting, which is also part of phase 4 clinical trials. In this lecture you will build upon that knowledge and further explore drug discovery and the phases of drug development. Throughout this lecture it will become clear that the clinical phases of drug development and forms the basis for evidence-based medicine. 3  Learning Outcomes At the end of this lecture, you should be able to:  Describe drug development in terms of natural products, semisynthetic and synthetic drugs  Describe what is meant by screening tests  Understand lead finding and lead optimisation  Describe what is meant by fortuitous drug discoveries  Explain the following steps when developing a drug:  Preclinical studies  Clinical trials and their 3 phases  New drug application and approval by controlling bodies  Post-marketing surveillance 4  Drug development The process for a new drug to enter the market is highly regulated In South Africa, the regulatory authority for drugs is SAHPRA (South African Health Products Regulatory Authority) SAHPRA assesses the applications for new drugs before they can be registered and sold in SA On average it can take 10-14 years to get a drug from the ideation phase to commercialisation The cost of research and development for new drugs is very high Image source: Gordon et al., 2018 Very few drugs end up making it to market, and on average it can cost $150 million per drug. 5  Drug development Investigational New Drug New Drug Application Image source: Gordon et al., 2018 – Figure 1 Brenner & Stevens’ Pharmacology. 2023. Chapter 4 Drug development and drug safety. Page. 35-36 Investigational new drug (IND) ; New drug application (NDA) https://www.ideagen.com/thought-leadership/blog/ind-and-nda-what-is-the- difference#:~:text=The%20difference%20between%20IND%20and%20NDA&text=It%20s tarts%20with%20an%20IND,to%20market%20in%20the%20USA. 6  3 components of a new drug development Candidate drug molecules are chosen on the Drug discovery basis of their pharmacological properties Various non-human studies (e.g. toxicity Pre-clinical testing, pharmacokinetic/pharmacodynamic development analysis and formulation) are performed The selected compound is tested for efficacy, Clinical side effects and potential dangers in development volunteers and patients Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 804. 7  Stages of a new drug development High throughput screening Image source: Duelen, R., Corvelyn, M., Tortorella, I., Leonardi, L., Chai, Y., Sampaolesi, M. 2019. Medicinal Biotechnology for Disease Modeling, Clinical Therapy, and Drug Discovery and Development. 10.1007/978-3-030-22141-6_5. Available online: https://www.researchgate.net/figure/Schematic-representation-of-the-drug-discovery- process-The-two-main-phases-discovery_fig2_335215729 Schematic representation of the drug discovery process. The two main phases, discovery and development, are articulated in sub-phases: for each sub-phase the major strategies and aims are listed (IND investigational new drugs) A ‘hit’ is a compound that displays the desired activity at the molecular target. High throughput screening (HTS) involves the screening of the entire compound library directly against the drug target 8  Stages of a new drug development Fig. 60.1 The stages of development of a ‘typical’ new drug, i.e. a synthetic compound being developed for systemic use. Only the main activities undertaken at each stage are shown, and the details vary greatly according to the kind of drug being developed. The stages of development of a ‘typical’ new drug, i.e. a synthetic compound being developed for systemic use. Only the main activities undertaken at each stage are shown, and the details vary greatly according to the kind of drug being developed. Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 804. 9  Origins of new drug compounds Natural products Occurring naturally in nature Semi-synthetic drugs Derived from natural products and undergo modification Synthetic drugs Also sometimes known as de novo drug design Most frequent origin for new drugs De novo drug design (DNDD) refers to the design of novel chemical entities that fit a set of constraints using computational growth algorithms. The word “de novo” means “from the beginning”, indicating that, with this method, one can generate novel molecular entities without a starting template 10  Natural products Natural products have proved to be a fruitful source of new therapeutic agents They tend to be derived mainly from fungal and plant sources Have been useful in the following fields: Anti-infec ve drugs → penicillin, streptomycin An cancer drugs → vincris ne, vinblas ne Immunosuppressant drugs → ciclosporin, sirolimus Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 806. 11  Semi-synthetic drugs Many naturally occurring compounds are a useful starting point for the development of new drugs Certain properties may make the natural compound unsuitable to use as is, for example: Chemical instability, poor oral absorption, unwanted adverse effects Modification of the natural compound can change the drug’s physicochemical properties to make it a better drug candidate for development Improve aspects such as: chemical stability, water solubility, strength of binding to the intended target Brenner & Stevens’ Pharmacology. 2023. Chapter 4 Drug development and drug safety. Page. 35 12  Synthetic drugs The need for development of a new drug arises when there is a disease or condition which requires drug therapy When synthesising a new drug, the first step is to identify a molecular target at which drug action is sought Known as ‘target selection’ Drug targets are usually functional proteins (e.g. receptors, enzymes, transport proteins) For example, the knowledge that breast cancer is often oestrogen- sensitive led to the development of aromatase inhibitors such as anastrozole, which exert their anticancer effect by preventing oestrogen synthesis Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 804. 13  Synthetic drugs ‘Lead finding’ involves identifying lead compounds that have the appropriate pharmacological activity at the identified molecular target and are amenable to further chemical modification Computer modeling of the drug and receptor can be used to predict whether the potential lead will be effective at the molecular target Large pharmaceutical development companies frequently maintain a growing collection of >1 million synthetic compounds Known as a compound library Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 805. 14  Synthetic drugs Using screening tests, assays are set up which test the interaction between the molecular target which was identified, and the large compound library in order to find a ‘hit’ A ‘hit’ is a compound that displays the desired activity at the molecular target Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 805. 15  Synthetic drugs The screening tests are often robot- assisted, high-throughput screens High throughput screening (HTS) involves the screening of the entire compound library directly against the drug target HTS assays are generally designed to run in plates of 384 wells and above, so it is capable of testing large numbers of compounds in a relatively short time period Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 805. Image source: https://www.medicilon.com/press-events/high-throughput-screening- service/ 16  Synthetic drugs ‘Hits’ detected in the initial screen often turn out to be molecules that have features undesirable in a drug, E.g. Excessive molecular weight or polarity, or possession of groups known to be associated with toxicity Computational ‘prescreening’ of compound libraries is often used to eliminate such compounds Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 805. Image source: https://multispaninc.com/drug-discovery-services-and-cell-screening/ 17  Synthetic drugs ‘Lead optimisation’ aims to increase the potency of the compound on its target and to optimise it with respect to other characteristics, such as selectivity and pharmacokinetic properties Tests applied include a broader range of assays in different systems, including: Studies to measure the activity and time course of the compounds in vivo Checking for unwanted effects in animals Evidence of genotoxicity Oral availability The objective of the lead optimisation phase is to identify one or more drug candidates suitable for further development in pre-clinical studies Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 806 18  Synthetic drugs Image source: https://www.bellbrooklabs.com/bellbrook-labs-expands-drug-discovery- services-portfolio-include-lead-discovery-services/ 19  Fortuitous drug discovery There are cases where a particular pharmacologic activity of a drug was discovered accidentally after the drug was administered to patients for other purposes For example: Clonidine was tested for treatment of nasal congestion when its profound antihypertensive effect was discovered. Now used for the treatment of hypertension Sildenafil (Viagra®) started as a drug candidate for treating hypertension when it was switched to the treatment erectile dysfunction Chlorpromazine (Largactil) the first antipsychotic medication was first used as an adjunct to anaesthesia to lower body temperature to treat shock ( as believed in 1952). It was found to produce disinterest without LOC in the patients and was tried on patients with SCZ with good effect Brenner & Stevens’ Pharmacology. 2023. Chapter 4 Drug development and drug safety. Page. 35. Examples of fortuitous drug discoveries: The antihypertensive effect of clonidine was discovered when the drug was tested for treatment of nasal congestion and a profound hypotensive episode ensued. This led to the subsequent development of clonidine for treating hypertension. More recently, the drugs to treat erectile dysfunction (VIAGRA, et al.) started as drug candidates for treating hypertension. The candidate drug was quickly switched to the treatment of ED program after an observant preclinical researcher noted tiny erections on the laboratory mice. The potential use of CPZ in psychiatry was first recognized by Henri Laborit (1952), a surgeon and physiologist in the French army, in the course of his research with artificial hibernation in the prevention of surgical shock. He employed the drug as an adjunct to surgical anesthetics (“anesthetic cocktail,” “lytic cocktail”) because of its body temperature lowering effect. He found that CPZ, in the dosage of 50 to 100 mg given intravenously, produced disinterest without loss of consciousness and with only a slight tendency to sleep. Laborit was able to persuade Hamon, Paraire and Velluz at the neuropsychiatric service of Val de Grâce, the military hospital in Paris, to try CPZ in the treatment of one of their agitated schizophrenic patients with good effect See this article:- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2655089/#:~:text=Chlorpromazine%20 20 was%20synthesized%20on%20December,(Charpentier%20et%20al%201952). 20 Phases of drug discovery Pre-clinical & clinical phasese YFRM202 21  Preclinical development The aim of preclinical development is to satisfy all the requirements that need to be met, before a new compound is deemed ready to be tested for the first time in humans This involves extensive testing on animals Based on the proven correlation between drug toxicity in animals and humans The work falls into four main categories: Pharmacokinetic Preliminary Chemical and Safety and toxicological pharmaceutical pharmacology pharmacodynamic testing development testing Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 806. 22  Preclinical development Safety pharmacology Pharmacological testing to check that the drug does not produce any obviously hazardous acute effects, such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes and ataxia Preliminary toxicological testing Animal studies to eliminate genotoxicity and to determine the maximum non-toxic dose of the drug Animals are checked for weight loss and other gross changes. At the end of the experiment post mortem studies are done to search for histological and biochemical evidence of tissue damage Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 806. 23  Preclinical development Pharmacokinetic and pharmacodynamic testing ADME studies in the species of laboratory animals used for toxicology testing, to link the pharmacological and toxicological effects to plasma concentration and drug exposure Chemical and pharmaceutical development Chemical and pharmaceutical development to assess the feasibility of large-scale synthesis and purification, to assess the stability of the compound under various conditions and to develop a formulation suitable for clinical studies. Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 806 24  Safety pharmacology TYPE OF STUDY METHOD OBSERVATIONS Acute toxicity Administer a single dose of the drug in two Behavioral changes, LD 50 ∗ , species via two routes. and mortality Subacute toxicity Administer the drug for 90 days in two Behavioral and physiologic species via a route intended for humans. changes, blood chemistry levels, and pathologic findings in tissue samples Chronic toxicity Administer the drug for 6–24 months, Behavioral and physiologic depending on the type of drug. changes, blood chemistry levels, and pathologic findings in tissue samples Teratogenesis Administer the drug to pregnant rats and Anatomic defects and rabbits during organogenesis. behavioral changes in offspring Mutagenesis Perform the Ames test in bacteria. Examine Evidence of chromosome cultured mammalian cells for chromosomal breaks, gene mutations, defects. chromatid exchange, trisomy, or other defects Carcinogenesis Administer the drug to rats and mice for Higher than normal rate of their entire lifetime. malignant neoplasms Brenner & Stevens’ Pharmacology. 2023. Chapter 4 Drug development and drug safety. Page 36. TABLE 4.1 Drug Toxicity Studies in Animals ∗ The LD 50 (the median lethal dose) is the dose that kills half of the animals in a 14-day period after the dose is administered. The Ames test is a commonly used method that utilizes bacteria to test whether a particular chemical can cause mutations in the DNA of the test organism. It is a biological assay that is formally used to assess the mutagenic potential of chemical compounds. Studies in animals may not reveal all the adverse effects that will be found in human subjects, either because of the low incidence of particular effects or because of differences in susceptibility among species. This means that some adverse reactions may not be detected until the drug is administered to patients. However, because studies of chronic toxicity of new drugs in animals may require years for completion, it is usually possible to begin human clinical studies while animal studies are being completed if the acute and subacute toxicity studies have not revealed any abnormalities in animals. 25  Pharmacokinetic studies Image source: Gordon et al., 2018 – Figure 2 ADME: absorption, distribution, metabolism, and excretion 26  Clinical development Clinical development consists of 3 phases of clinical trials in humans: Performed on a small group (20-80) of healthy volunteers Assess for toxic effects (e.g. hepatic, cardiovascular, respiratory, renal function) Assess tolerability (e.g. unpleasant symptoms like Phase I drowsiness, headache) Pharmacokinetic properties (e.g. oral bioavailability, half- life, kinetic profile) Pharmacodynamics: proof-of-concept (does the drug treat what it is intended to? does the effect change with dose?) Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 807 27  Clinical development Clinical development consists of 3 phases of clinical trials in humans: The first studies to be performed in human subjects who have the particular disease that the drug is designed to target. Performed in approximately 100-300 people Phase II Provides a preliminary assessment of the drug's efficacy and safety in affected individuals Helps to establish a dosage range at which the drug is effective in treating the disease for further clinical studies (Phase III) Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 807. Phase II studies are performed on groups of patients (normally 100–300) and are designed to determine clinically beneficial pharmacodynamic effects in patients, and if this is confirmed, to establish the dose regimen to be used in the definitive phase III study. Often, such studies will cover several distinct clinical disorders (e.g. depression, anxiety states and phobias) to identify the possible therapeutic indications for the new compound and the dose required. When new drug targets are being studied, it is not until these phase II trials are completed that the team finds out whether or not its initial hypothesis was correct, and lack of the expected effect is a common reason for failure. 28  Clinical development Conducted to compare the safety and efficacy of the drug being investigated with that of commonly used alternative drugs, treatment approaches or placebos which are already being used Phase 3 is key in establishing whether the drug is truly safe and effective and also provides the basis for Phase labelling instructions III Consist of definitive double-blind, randomised trials, commonly performed as multicentre trials on thousands of patients (1000-5000) These are extremely costly, difficult to organise and often take years to complete, particularly if the treatment is designed to retard the progression of a chronic disease Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 807 It is not uncommon for a drug that seemed highly effective in the limited patient groups tested in phase II to look much less impressive under the more rigorous conditions of phase III trials. 29  Summary of clinical trial phases Image source: Gordon et al., 2018 – Table 1 30  Approximate costs of drug development Phase 1 Phase 3 Preclinical clinical Phase 2 clinical clinical studies: studies: studies: studies: R15-20 mil per R50-100 mil per R5-10 mil per R300-500 mil compound study study per study Image source: Gordon et al., 2018 – Table 1 31  Regulatory approval At the end of phase III clinical trials, the drug developer will submit a new drug application (NDA) to SAHPRA for licensing of the drug The dossier required for this licensing and registration is a massive and detailed compilation of preclinical and clinical studies’ data, as well as the proposed labeling and clinical indications for the drug. Evaluation by SAHPRA normally takes a year or more Further delays often arise when aspects of the submission must be clarified or more data are required Once approval has been obtained, large scale manufacture of the drug can begin Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 808. SAHPRA 32  Post-marketing surveillance Also known as Phase IV clinical studies Once a drug is approved by SAHPRA and the drug is available on the market to be sold to the public, obligatory post-marketing surveillance takes place Phase IV studies are designed to detect any rare or long-term adverse effects resulting from the use of the drug in a clinical setting in many thousands of patients Such events may necessitate limiting the use of the drug to particular patient groups, or even complete withdrawal of the drug from the market Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 808. This is where reporting of adverse drug reactions is important so that SAHPRA and the manufacturer is aware of potential issues. The form for this reporting is available from SAPHRA – see previous lectures. 33  Summary of drug development Brenner & Stevens’ Pharmacology. 2023. Chapter 4 Drug development and drug safety. Page. 35. Fig. 4.1 Steps in the process of drug development in the United States. IND, Investigational new drug; NDA, new drug application. 34  Checklist Can you...  Describe drug development in terms of natural products, semisynthetic and synthetic drugs?  Describe what is meant by screening tests?  Understand lead finding and lead optimisation?  Describe what is meant by fortuitous drug discoveries?  Explain the following steps when developing a drug  Preclinical studies?  Clinical trials and their 3 phases?  New drug application and approval by controlling bodies?  Post marketing surveillance? 35  References Brenner & Stevens’ Pharmacology. 2023. Chapter 4 Drug development and drug safety. Page 35-45. Duelen, R., Corvelyn, M., Tortorella, I., Leonardi, L., Chai, Y., Sampaolesi, M. 2019. Medicinal Biotechnology for Disease Modeling, Clinical Therapy, and Drug Discovery and Development. 10.1007/978-3-030-22141-6_5. Available online: https://www.researchgate.net/figure/Schematic-representation-of-the-drug-discovery-process- The-two-main-phases-discovery_fig2_335215729 Gordon, R., Shamley, D., McLaughlin, R. 2018. Pharmaceutical products: an innovation guide from lab to commercialization. Available online: https://www.sarima.co.za/wp-content/uploads/2019/01/r2m_guide_02.pdf Rang and Dale’s Pharmacology. 2024. Chapter 60 Drug discovery and development. Page 802-811. 36  Feedback Please be kind enough to take a minute and rate this lesson and provide a little feedback to help us gain a better understanding of your learning experience. Let us know what you really enjoyed and what we can do better for you. Click on the link at the bottom of the lesson page on I-learn to provide feedback for this lesson. +- (2mins) 37 38 39