Significance of DMPK in drug discovery.pptx

1.Introduction
2. What is DMPK
3. Objectives/ Significance of DMPK
4. Why DMPK
5. Role of USFDA
6. ADMET/PK
7. Bioanalysis
8. Conclusion

1. SIGNIFICANCE OF DMPK IN DRUG DISCOVERY PRIYANSHA SINGH B. Pharm, M.S. (Pharm.)- Pharmacology & Toxicology Understanding the Pillars of Drug Development

2. INTRODUCTION Drug discovery is the systematic process of identifying and developing therapeutic compounds to address specific diseases or medical conditions. Effective drug development is essential for improving health, addressing unmet medical needs, driving economic growth, advancing scientific knowledge, and ensuring global health security. It plays a vital role in enhancing and sustaining human well-being on a global scale. The inclusion of DMPK in drug development is integral- optimization of drug dosage, enhances safety, influences formulation, provides early insights, ensures regulatory compliance, and supports the development of personalized medicine, ultimately contributing to the overall success of effective drug development.

3. The drug discovery/development process is a long, hard one

4. Basic overview of drug discovery

5. WHAT IS DMPK?

6. KEY OBJECTIVES OF DMPK- Supporting medicinal chemistry in assisting hit cluster evaluation and ranking Assessing the optimization potential of the compounds in each cluster Predicting a human efficacious dose Selecting appropriate compounds to progress into preclinical development 

7. WHY DMPK? DMPK studies assess a drug's absorption, distribution, metabolism, and excretion (ADME) properties, as well as its pharmacokinetic (PK) properties. Drug metabolism and pharmacokinetics (DMPK) studies are important in drug discovery and development because they help optimize drug-like properties.   DMPK studies help researchers rank compounds based on their pharmacokinetic properties, which include absorption, distribution, clearance, and elimination.  DMPK helps to identify drugs that are likely to be suitable for advancement through the drug development process  DMPK studies also help drug developers evaluate a drug candidate's intrinsic properties. This helps ensure that the drug can be cleared from the body without producing harmful byproducts or reaching dangerous exposure levels.  DMPK studies also help predict drug metabolism and pharmacokinetics in humans. Successful predictions can reduce the rate of attrition during drug discovery and development. 

8. IMPORTANCE OF DMPK It is estimated that close to 50% of drug candidates fail because of unacceptable efficacy and that up to 40% of drug candidates have failed in the past due to toxicity. Drugs such as mibefradil, soruvidine, and phenylpropanolamine hydrochloride have been pulled off the market due to drug-drug interactions or toxicity. It has become obvious to both regulators and drug makers that in addition to pharmacological properties, ADME/Tox studies play a crucial role in the success of a drug candidate. Due to this impact on eventual success, these studies now occur early in the drug discovery process.

9. ROLE OF THE USFDA IN DMPK STUDIES

10. ADMET studies

11. GOAL OF ADMET STUDIES

12. PK STUDIES Pharmacokinetics is a broader term that encompasses ADME and focuses on the quantitative analysis of the drug's movement within the body. PK involves studying the time course of drug absorption, distribution, metabolism, and excretion (ADME) and how these processes affect the concentration of the drug in various tissues over time. PK parameters include Cmax (maximum concentration), Tmax (time to maximum concentration), AUC (area under the concentration-time curve), and others.

13. WHY PK? Enable design and selection of the molecule with the best overall profile to achieve realistic dosing regimen (dose size and frequency of administration). Enable appropriate preclinical and clinical characterization of a molecule to enable it to become a drug (safety and efficacy considerations). PK scientists role is fundamentally focused on ACCURATE PREDICTION of dose, efficacious systemic exposure, fraction absorbed, and clearance of NMEs to enable successful testing of mechanism of action in clinical development.

14. WHAT ARE PRECLINICAL STUDIES? E xperiments that are performed to learn about the safety and effectiveness of a drug candidate before testing it on humans. 

15. MOST POPULAR DMPK STUDY AREAS In vitro and in vivo studies are conducted to enable a drug developer to make a go-no-go decision regarding if a drug should be selected as a drug candidate, and moved into late-stage preclinical and clinical programs. ADME properties allow drug developers to understand the safety and efficacy of a drug candidate, and are necessary for regulatory approval.

16. STANDARD IN-VITRO ADME ASSAYS FOR DRUG DISCOVERY

17. STANDARD IN-VIVO PK ANALYSIS FOR DRUG DISCOVERY During discovery, as well as in late stage preclinical and non-clinical studies, in vivo studies are conducted to evaluate pharmacokinetic (PK) properties.  In vivo  PK studies are conducted with Association of Assessment and Accreditation of Laboratory Animal Care (AAALAC) accredited animals are employed to generate PK data to evaluate properties such as drug clearance, bioavailability, exposure, half-life, and distribution volume. These studies include a mix of non-GLP and GLP toxicology studies. Routes of elimination Species & tissues Analysis & interpretation Oral Intravenous Intraperitoneal Subcutaneous Intramuscular Osmotic mini-pumps Inhaled Intranasal/intratracheal Mouse, rat Hamster, rabbit, Guinea pig Dog/primate/minipig Plasma/blood/CSF Tissues (organs/tumour) Bile & urine (elimination) Non compartmental/ compartmental analysis Selection of regimen & dose for preclinical PD & efficacy studies Mechanistic PK/PD (understanding target engagement) Dose to man prediction

18. IN-VIVO ADME STUDIES In vivo ADME studies are generally conducted with radioactive labels on the target test article to provide quantitative information on the mass of distribution, rate of metabolism, and pathway of excretion for the test article and its metabolites. They provide quantitative information on the following: Mass of distribution Rate of metabolism Pathway of excretion for the test article and its metabolites Extent of metabolism Circulating metabolites 

19. IN VIVO ADME TESTING STUDIES Name Description Absorption: Pharmacokinetics In vivo ADME studies start by looking at the pharmacokinetics (PK) of the test article, the characterization of the time course of the test article being absorbed, distributed, metabolized and excreted. To characterize the movement of the test article into the body (absorption), researchers analyze the test article concentration in plasma, blood and tissues. Distribution: Quantitative Whole Body Autoradiography (QWBA) QWBA determines a test article’s tissue distribution, both visually and quantitatively. A living system is dosed with a radiolabeled test article and then radioactivity measured through cross section slides to show distribution in tissues over time.

20. Name Description Excretion: Mass Balance & Bile Duct Cannulated (BDC) Mass balance and BDC studies  characterize how the test article is eliminated from the test system – specifically the test article’s excretion path and rate. The test system or in vivo system and samples are analyzed for radioactivity, providing insight into how the test article is eliminated from the body. Metabolism: Metabolic Profiling To understand the metabolic pathways in the animal system, researchers collect urine, feces and bile samples from mass balance studies and send them for  metabolic profiling and identification . These studies are used to discover what metabolites are formed following test article distribution to ensure that there are not any potentially harmful human-specific metabolites. Human AME Studies The previously listed in vivo ADME tests provide the data needed in preparation for  human radiolabel absorption, metabolism, excretion (AME) studies . Human AME studies help drug developers understand the nature and amounts of drug metabolites formed in the human body, and the data reveals the biotransformation, disposition, and clearance of the parent test article and its metabolites. These studies are crucial to guide the design of clinical drug-drug interactions and the dose level selection in phase II and II clinical trials.

21. ADME PK Like PK, ADME studies are often performed in living organisms to capture the complex interactions of a drug with the body. This involves administering a drug to animals or humans and monitoring its fate regarding absorption, distribution, metabolism, and excretion. Pharmacokinetics is a broader term that encompasses ADME and focuses on the quantitative analysis of the drug's movement within the body. PK studies are primarily conducted in living organisms to understand the time course of drug concentration in the bloodstream and various tissues. In vivo studies involve administering drugs to animals or humans and monitoring the drug's absorption, distribution, metabolism, and excretion over time. In vitro studies are crucial in certain aspects of ADME research. For example, cell culture models, artificial membranes, or isolated enzymes can be used to study specific processes like drug permeability, metabolism, or protein binding. In vitro methods may be used in specific aspects of PK studies, such as assessing drug metabolism using isolated enzymes or hepatocytes, but the overall PK analysis is usually conducted in vivo. Absorption: The process by which a drug enters the bloodstream from its site of administration (e.g., the gastrointestinal tract for orally administered drugs). Distribution: Describes how a drug is transported through the bloodstream to its target tissues and organs, as well as how it may be distributed within those tissues. Metabolism: Involves the chemical transformation of a drug by enzymes, usually in the liver. Metabolism can convert the drug into inactive or active metabolites. Excretion: Refers to the elimination of a drug or its metabolites from the body, typically through urine or feces. The kidneys and liver are major organs involved in drug excretion. PK involves studying the time course of drug absorption, distribution, metabolism, and excretion (ADME) and how these processes affect the concentration of the drug in various tissues over time. PK parameters include Cmax (maximum concentration), Tmax (time to maximum concentration), AUC (area under the concentration-time curve), half life, volume of distribution, clearance, bioavailability

22. SIGNIFICANCE OF DMPK IN DOSE DESIGN

23. SIGNIFICANCE OF DMPK IN RESPONSE PREDICTION

24. ADME/PK Input to Drug Discovery and Development

25. BIOANALYSIS Bioanalysis is a technique used in the early stages of drug development to measure the concentration of drugs and their metabolites in biological fluids. This information is used to support drug discovery programs and study the pharmacokinetics of chemicals in living cells and animals. Bioanalysis is used to determine the concentration of drugs and their metabolites and biomarkers in: Physiological fluids, such as blood, serum, plasma, urine, and cerebrospinal fluid Tissue, such as skin Tumor biopsies  Bioanalysis is an integrated technique used in the preclinical stages of the drug discovery process to support the clinical phases. Bioanalysis can handle analytes of diverse types such as small molecules to as large as bispecific antibodies to protein constructs

26. ROLE OF BIOANALYSIS IN DMPK Bioanalysis can also be used to provide reasonable values of concentrations and/or exposure. These values can then be used to form a scientific basis for lead series identification and/or discrimination amongst several lead candidates.  Some commonly used analysis methods include: Chromatography: gas chromatography (GC), high performance liquid chromatography (HPLC), chromatography-mass spectrometry (LC-MS, LC-MS-MS, GC-MS, GC-MS-MS), etc. Tandem mass spectrometry (MS/MS)

27. ADME/PK Science Spans from Mechanism to Market

28. CONCLUSION The science of ADME/PK is broad and covers many aspects from early idea to late into development. Understanding ADME principles aids molecular design and data interpretation helping identify the best molecule for success.