Molecule to medicine
Download as PPTX, PDF3 likes416 views
1) The process of bringing a new medicine from initial discovery to patient use (molecule to medicine) is a long, complex, and expensive process involving target identification, preclinical testing, clinical trials, and regulatory review and approval. 2) Preclinical testing involves evaluating a molecule's pharmacokinetics, pharmacodynamics, safety, and toxicity in cell and animal studies. Positive preclinical results allow filing an Investigational New Drug (IND) application to begin human clinical trials. 3) Clinical trials are conducted in four phases to evaluate a drug's safety, efficacy, side effects, and optimal dosing in humans. The entire development process from discovery to approval takes 8-12 years and costs over $1
Molecule to medicine
- 1. Molecule to medicine Dr.Meharban , MSc, Ph.D. Assistant Professor, Department of Pharmacology Vydehi Institute of Medical Sciences & Research Centre PHARMAQUEST-2021
- 3. Introduction • The drug discovery and development process (i.e molecule to medicine) – Discovery research – Preclinical testing – Investigational new drug (IND) applications – Completed clinical testing before marketing approval from the FDA.
- 4. Introduction • The overarching goal – More efficient – Safer treatments to the patients – Quickly as possible after a thorough medical evaluation • Very lengthy, long duration, involves multi discipline people to bring a medicine from molecules discovery • Very expensive with lot of uncertainty and failures
- 5. Site Selection Molecules to medicine: Process Target identification: Choose a molecule in the body to target with a drug; often a protein or receptor Target validation: Test the target and confirm its role in the disease pathology Lead generation: Find lead compound that could become a drug through medicinal chemistry optimization Early safety testing: Initial tests on lead compounds, including pharmacokinetics, by experiment and/or computer modelling assess the safety risk Lead optimisation: Alter the structure of lead candidates to improve properties; this may include formulation, delivery mechanism and scale-up. Discovery research Preclinical research Clinical research Regulatory review & approval Pharmacokinetic study: Asses the exposure across preclinical species and derive the pharmacokinetic parameters Pharmacodynamic study: Confirm the efficacy in relevant disease model in preclinical species Chemistry, manufacturing and control( CMC): Robust chemical synthesis in place to supply large qty of drug substance Identified suitable formulation to convert drug substance into drug product for IND enabling studies and clinical testing Safety and toxicology evaluation: To assess the safety of preclinical candidate in rodents and non rodents to build body evidence to take compound for human testing Clinical trial exceptions (CTX) applications File CTX with appropriate authorities before clinical testing can begin. Phase 1 clinical trial Initial human testing in a small group of healthy volunteers. Phase 2 clinical trial Test in a small group of patients. Phase 3 clinical trial Test in a large group of patients to show safety and efficacy. Marketing authorisation application Apply to appropriate authorities for approval. Manufacturing Begin full-scale production. On-going studies and Phase 4 trials Continuing monitoring and checking of the drug in use.
- 6. The essence of Drug Discovery 6 Safe Effective Affordable Profitable Globally relevant Sustainable Cost effective Potent Safe Patentable Hospital Bed Lab Bench De-risk Increase Probability of Success
- 7. Drug Discovery : timelines 1 Drug Approve d Lead Opt 1000 – 5000 compounds Pre-Clinical 5-20 compounds Clinical Trials 2-3 compounds FDA Review Expenses ~8-12 years 1-3 years 6-10 years
- 8. Molecule generation – Random Screening • HTS - using large compound collection in high throughput mode – Molecular Manipulation • Modification existing drug or leads natural product – Molecular Designing • Structure based design using crystal bound ligand structure or using enzyme substrate or natural agonist of receptor or modification natural neurotransmitter – Drug Metabolites • Knowledge based modification metabolites – Serendipity • Identification lead by accident, e.g. Viagra
- 9. Lead generation examples Natural product source Lead Drug Lead Drug Drug Drug Rational design using 3D- structure of enzyme
- 10. Lead optimization- fine tuning of properties • Optimizing chemical lead for clinical trial is commonly referred to as lead optimization • The refinement in structure is necessary in order to improve • Potency • Oral Availability • Selectivity • pharmacokinetic properties • safety
- 11. Hameed P., et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun 6, 6715 (2015) MMV253: Optimized lead from HTS hits MMV253 is completed phase-1 study and entering phase-2 trial
- 12. In-vitro studies • Drug affinity: Ability of drug to bind to its biological target (receptor, enzyme, transport system, etc.) • Selectivity- Drug should bind to specific receptor site on the cell (eg. Atenolol) • Solubility and permeability: Helps to assess the drug absorption • Metabolism and transporter studies: Asses the metabolic stability and elimination characteristic of molecules • Off –target selectivity testing : Screening of molecules against various secondary pharmacology targets ( Cardiac ion channels, enzymes, receptor and kinases) to build selectivity and reduce safety risk
- 13. In vivo studies • Its experimentation using a whole, living organism. • Gives information about, • Pharmacokinetic profile (rodents and non rodents) Magnitude of pharmacological effect depends on drug concentration at its site of action. • Pharmacodynamic profile Establishes effectiveness of drug in preclinical animal disease model to demonstrate proof concept e.g SCID mice for malaria, NOD mice- Diabetes, Syngeneic mice tumor model for Cancer PMID: 30131376
- 14. Safety and toxicity: IND package Readout and risk assessment Cardiovascular safety • Conscious dog telemetry to assess the effect candidate drug on ECG changes, proarrhythmic and QT prolongation risk Genetic toxicity • Ames test to assess and rule out mutagenic potential drug candidate • in vitro micronucleus to rule out genetic toxicity in vitro under GLP conditions • in vivo micronucleus and comet test to rule in vivo genotoxic potential drug candidate if it is found to be positive under in-vitro conditions General and Organ toxicity in rodents and non rodent species • 14/28-day repeat dosing of compounds in rats and dog to determinate the no observed adverse effect level(NOAEL) using clinical observations and histopathological findings • Helps to study toxicokinetic and calculate therapeutic margins for human clinical trials • Identification monitorable safety risk( Reversible elevation of liver enzymes) Respiratory toxicity • To assess the effect of drug candidate on respiration rates and volumes Central nervous system toxicity • To assess the impact of drug candidate on behaviour, sensory / motor responses and body temperature and associated risk
- 15. Investigational new drug application Preparing for an IND Submission Proof-of-concept scientific data • Should include considerations of product activity, ability to replicate results and a reasonable explanation how the product will prevent, diagnose, treat or cure disease A target clinical Indication • Disease indication for which the intended drug developed for the treatment Animal toxicology data • Usually obtained in two species that supports the dose, dosing schedule, administration, and study duration proposed in the clinical protocol Manufacturing process • Provides evidence that product is manufactured according to GMP, including analytical tests results confirming the quality of the product several batches of the product Stability Information • Data demonstrating the stability of the drug, under defined storage conditions, or the period of use for the clinical trial Clinical plan/ protocol • Clinical trial design to assess the safety and tolerability of clinical candidate in human Request submitted to the FDA to allow human exposure limit to the experimental drug
- 16. 16 Phases clinical trials FDA Phases ICH Types Objectives Phase I Human Pharmacology •Assess tolerance •Drug metabolism and drug interaction •Estimate drug activity Phase II Therapeutic Exploratory •Assess use for target indication •Estimate dosage for subsequent studies Phase III Therapeutic Confirmatory •Confirm efficacy •Collect information for assessing risk /benefit relationship to support licensing •Monitor side effects Phase IV Therapeutic Use Identify less common adverse effects Refine dosing recommendations Refine risk benefit relationship in general or special populations Approved for testing in human Submitted for review and approval Approved for human use Post Marketing Surveillance Pharmacovigilance
- 17. Pre-IND meeting IND submission Pre NDA meeting NDA Submission Approval Stages of FDA Review Engage regulatory authority (FDA) to seek opinion on preclinical data package to incorporate into IND Submission of NDA application post phas-3 outcome for review and approval for human use Involve regulatory agency for data review post phase-2b/III to elicit the response and suggestion for NDA application Submission of IND package for review, allow human exposure limit and approval for testing in human Committee reviews and majority opinion decides approval for human use 30 day