Drug Development Process Lecture III

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  1. Pathophysiology
    Pathophysiology or Physiopathology is a convergence of pathology with physiology.

    Pathology is the medical discipline that describes conditions typically  observed during a disease state, whereas physiology is the biological discipline that describes processes or mechanisms operating within an organism.

    Pathology describes the abnormal or undesired condition, whereupon pathophysiology seeks to explain the physiological processes or mechanisms whereby such condition develops and progresses.

    Pathophysiology can also mean the functional changes associated with or resulting from disease or injury.
  2. What is a monoclonal antibody?
    A monoclonal antibody is a laboratory-produced molecule that's carefully engineered to attach to specific defects in your cancer cells. Monoclonal antibodies mimic the antibodies your body naturally produces as part of your immune system's response to germs, vaccines and other invaders.

    How do monoclonal antibody drugs work?

    When a monoclonal antibody attaches to a cancer cell, it can:

    Make the cancer cell more visible to the immune system. The immune system attacks foreign invaders in your body, but it doesn't always recognize cancer cells as enemies. A monoclonal antibody can be directed to attach to certain parts of a cancer cell. In this way, the antibody marks the cancer cell and makes it easier for the immune system to find.

    Block growth signals. Chemicals called growth factors attach to receptors on the surface of normal cells and cancer cells, signaling the cells to grow. Certain cancer cells make extra copies of the growth factor receptor. This makes them grow faster than the normal cells. Monoclonal antibodies can block these receptors and prevent the growth signal from getting through.

    Stop new blood vessels from forming. Cancer cells rely on blood vessels to bring them the oxygen and nutrients they need to grow. To attract blood vessels, cancer cells send out growth signals. Monoclonal antibodies that block these growth signals may help prevent a tumor from developing a blood supply, so that it remains small. Or in the case of a tumor with an already-established network of blood vessels, blocking the growth signals could cause the blood vessels to die and the tumor to shrink.

    Deliver radiation to cancer cells. By combining a radioactive particle with a monoclonal antibody, doctors can deliver radiation directly to the cancer cells. This way, most of the surrounding healthy cells aren't damaged. Radiation-linked monoclonal antibodies deliver a low level of radiation over a longer period of time, which researchers believe is as effective as the more conventional high-dose external beam radiation.
  3. Angiogenesis
    Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. Antiangiogenesis drugs disrupttumor’s blood supply
  4. Metastasis
    Metastasis, or metastatic disease, is the spread of a cancer from one organ or part to another non-adjacent organ or part.

    Cancer occurs after a single cell in a tissue is progressively genetically damaged to produce cells with uncontrolled proliferation. This uncontrolled proliferation, mitosis, produces a primary tumor. The cells which constitute the tumor eventually undergo metaplasia, followed by dysplasia thenanaplasia, resulting in a malignant phenotype. This malignant phenotype allows for intravasation into the circulation, followed by extravasation to a second site for tumorigenesis.

    Some cancer cells acquire the ability to penetrate the walls of  lymphatic  and/or blood vessels, after which they are able to circulate through the bloodstream  (circulating tumor cells) to other sites and tissues in the body. This process is known (respectively) as lymphatic or hematogenous  spread. After the tumor cells come to rest at another site, they re-penetrate the vessel or walls and continue to multiply, eventually forming another clinically detectable tumor. This new tumor is known as a metastatic (or secondary) tumor. Metastasis is one of three hallmarks of malignancy (contrast benign tumors)
    • What is optimization of SAR?
    • – Chemical alteration of an early lead drug candidate molecule to enhance one or more aspects of the pharmacological activity of the molecule
    • – For example, to enhance:
    • • Potency
    • • The safety profile, i.e., to make the molecule less cytotoxic or less toxic in animals
    • • The pharmacokinetic/ADME profile
    • – E.g., to improve oral absorption (oral bioavailability), to alter the metabolite profile

    • Who is involved in performing optimization of SAR?
    • – Medicinal chemists (chemistry) & biologists (test the altered molecule)
    • The FDA will not allow a drug candidate to be administered to humans until its short term effects are studied in lab animals. In addition, some invitro safety data will be required. Once clinical studies begin, additional in vitro and in vivo safety data (in animals) will be required, and these studies may run concurrently with clinical studies. Generally, most studies,if not all, which provide in vitro and animal safety data must be completedby initiation of Phase III Clinical Studies and certainly by submission of theNDA.

    • Although non clinical studies are not the perfect predictors of the effect of the test drug in humans, these systems currently provide the best practical experimental models to obtain information on how the drug may act in humans.

    -FDA will use information from these studies to make“go/no go” decisions regarding studies in humans.
    • The FDA will recommend what non clinical test data are needed to show that the drug candidate is sufficiently safe for initial and continued testing in humans. (At the Sponsor’s request, the agency will provide advice on the adequacy of the non clinical studies BEFORE these studies are initiated.)

    • The FDA sets the minimum standards for labs conducting non clinical toxicity testing via Good Laboratory Practice (GLP)* guidances.

    • Why is this important? Because data from non clinical studies, especially GLP toxicology studies, support the IND Application, which in part provides FDA with confidence on the safety of the drug candidate for the first clinical studies in humans.
    • Chemical structure of the drug: similarity to approved drugs w/known safety profiles

    • Proposed indication in humans: mild/self-limiting disease vs. life threatening disease

    • Target population: infants/children, elderly, women of child bearing age

    • Special characteristics of a drug’s pattern of use; e.g., if a drug is likely to be prescribed as a concomitant medication

    • Route of administration of drug

    • Length of time the drug is to be taken by patients: short term vs.long term
    • Pharmcodynamics (PD): the action a drug has on its target and within the body. PD effects can be positive as in providing efficacy, but also negative as in promoting the side effect profile associated w/ drugs.
    • – Mechanism of action (MOA) & characterization studies (how does the drug work?)
    • – Dose-response studies
    • – Toxicity studies (in vitro & in vivo [animals]; see examples below)

    • Pharmacokinetics (PK): actions of the body on the drug
    • – ADME parameters: adsorption, distribution, metabolism, excretion

    • Toxicity/Toxicology/Toxicokinetics
    • – Acute, subacute, chronnic tox studies
    • – Carcinogenicity studies
    • – Genotoxicity & reproductive tox studies
    • Why is understanding the PK properties of a drug candidate critical for drug development?
    • – One cannot interpret toxicologic findings of the parental molecule or its metabolites without knowing what concentrations of the drug candidate (or its metabolites) cause toxicity
    • – It is essential to predict drug-drug, drug-metabolite, and metabolite-metabolite interactions: whether the candidate drug can be given safely with concomitant medications
    • – Necessary to determine plasma/tissue levels of drug candidate to guide dose and frequency of dose for clinical studies in humans(especially for Phase I studies)
    • – To determine how long a drug stays within the body; if it concentrates in an organ or tissue; its principal route of elimination from the body
    • – FDA requires these studies prior to initiating human clinical trials
    • • Bioavailability is useful in characterizing exposure to drugs that are administered orally and topically (and some other routes) in which absorption and systemic distribution of the drug in the blood is essential for the drug to provide efficacy.
    • • Bioavailability is dose-independent as long as one is dosing a compound within the range in which the compound can be absorbed. Therefore,increasing the dose will increase the exposure to the drug, but the bioavailability will be the same as the lower dose.
    • • Drugs with relatively lower oral bioavailability must be dosed more frequentlycompared to drugs with relatively higher oral bioavailability.
    • • Oral bioavailability may vary with different animal species; e.g., F in mice,rats, dogs, and humans may be different. Therefore, F determined in animals may not necessarily be predictive of F in humans.
  12. Factors affecting oral bioavailability
    • – The drug formulation (e.g., capsule, tablet, liquid)
    • – Dissolution properties of the drug formulation
    • – Absorption characteristics of the drug molecule
    • – Presystemic metabolism (in the GI tract)
    • – Acid lability of the drug molecule
    • – First pass metabolism
    • Toxicokinetics is the “marriage” between toxicology and pharmacokinetics (PK). Toxicokinetics addresses the PK parameters underlying toxicity findings.

    E.g., if toxicity is observed in a particular tissue or organ, one would want to know the concentration of the drug present in the tissue or organ. Likewise, what plasma concentrations are associated with toxicity?
    • • Drug not absorbed/poorly absorbed in animal
    • • Drug absorbed but subject to significant first pass metabolism
    • • Drug absorbed but not distributed/poorly distributed to target tissue
    • • Drug rapidly metabolized to inactive metabolite
    • • Drug rapidly eliminated from the body
    • • Experimental conditions between in vitro and in vivo too different
    • • Experimental endpoints between in vitro and in vivo different or are measured differently
    • • In vitro data cannot predict movement of drug between different compartments
    • • Bioavailability, Cmax, and/or t½ not predicted by in vitro systems
    • • Drug destroyed by stomach acid (if administered orally)
    • • Drug metabolized in gut by intestinal flora
    • • Drug formulation/delivery vehicle not appropriate for animal
    • • Drug not sufficiently potent
    • • Disease severity overwhelms drug
    • • Dose and/or regimen insufficient to demonstrate efficacy
    • • Animals subject to circadian rhythms that may affect drug activity
    • • Sex or age specifications of animal model
    Biotransformation (BT) of a drug is a chemical change to the drug molecule carried out by any of various enzyme systems. Enzymes altering the chemical structure of a drug can be associated with a variety of cells in the human body or by the microorganisms in our intestinal tract.

    • BT of a drug may be necessary to make it active as in the case with a pro drug. In other instances, BT may be necessary to allow a drug to be excreted by the kidneys. Sometimes, a drug metabolite will be more potent or more toxic that the parental molecule
  16. Sites of Biotransformation
    – The liver is the major site of drug metabolism because it has a high concentration of metabolizing enzymes, but virtually every cell in the body is capable of metabolizing a drug. Other organs with significant metabolizing activity include the kidneys, GI tract, skin, and lungs.
  17. Hepatic Enzymes Responsible for Biotransformation of Drugs
    • – Cytochrome P450 Monooxygenase System of Enzymes
    • • The P450 gene family has evolved to metabolize environmental chemicals, food (plant)toxins, and now drugs. 
    • • Twelve P450 gene families have been discovered in humans with each family divided intosubfamilies.   
    • • The first three families (CYP1, CYP2, & CYP3) encode the enzymes involved in the majority of all drug biotransformations, while the enzymes from the remaining families are involved in the metabolism of endogenous molecules such as steroids, fatty acids.
  18. Types of Biotransformation Reactions
    – Enzymatic activity activates (e.g., prodrug) or inactivates the drug molecule

    • – Enzymatic activity conjugates another molecular entity within the body to the drug molecule via a covalent linkage. These transformations of the drug generally make a poorly water soluble drug relatively more water soluble; this change promotes excretion of the drug via the kidneys. The conjugation reaction also usually inactivates the drug.
    • Example conjugates include:
    • • Glucuronic acids
    • • Sulfate
    • • Glutathione
    • • Amino acids
    • • Acetate

    – An exception to conjugation causing loss of drug activity is the glucuonide conjugate of morphine, which is more potent than the unconjugated parent molecule.

    – Sometimes, a drug conjugate secreted into the intestinal tract (via the gallbladder) is cleaved by microbial enzymes such that the parental drug is released for re-absorption into the blood stream (Enterohepatic Recirculation).
    • • Induction of P450 enzymes
    • – Of concern since suggests drug interacts with genes to up regulate P450 genes

    • • Inhibition of P450 enzymes
    • – Competition between two or more drugs for the same CYP enzyme; can lead toserious consequences in regard to drug toxicity

    • • Genetic Polymorphisms
    • – Mutations in P450 genes that result in enzymes with functional deficienciescompared to normal, non polymorphic genes
    • – Genetic polymorphisms in P450 genes (or other genes involved in drug metabolism)manifest in individuals or ethnic groups who are unable to normallymetabolize drugs
    • – Trying to understand how genetic polymorphisms affect drug metabolism and drug activity in different human ethnic groups is the science of PHARMACOGENOMICS
    • Pharmcogenomics uses genetic information about a specific human orethnic group to understand/predict how a person/group will respond to agiven drug in regard to safety and efficacy

    • Currently, pharmacogenomics is a “hot” area for research activity as theoretically it can help biopharmaceutical companies select subjects for clinical studies who will have a greater probability of achieving efficacy and tolerating the drug

    • • Data on gene sequences from the HUMAN GENOME PROJECT are providing genetic information to make pharmacogenomic decisions
    • Example: Suppose Drug X, which is inactive, must be metabolized to X1 by the P450 liver enzyme CYP2D6.
    • • The Major Provisions of GLP
    • – Organization & personnel
    • – Testing facility
    • – Operation of the testing facility
    • – Test & control article characterization
    • – The protocol & conduct of the non clinical lab study
    • – Records & reporting
    • – Design & maintenance of equipment

    • • Organization and Personnel
    • – General personnel qualifications
    • – Must have a Study Director
    • – Quality assurance unit
    •     • At least one individual is assigned to           assess QA & cannot directly participate         in study
    •     • Record equipment maintenance, study          inspections, reports to facility                      management
    •     • A signed QA report is filed with each           study report to confirm inspections &           that study done according to protocol

    • • Testing Facility
    • – Must be of adequate size & have equipment needed to conduct the studies
    • – Regulated environmental controls for air quality, avoidance of contaminants, etc.

    • • Organization of Testing Facility
    • – Must have Standard Operating Procedures (SOPs)
    • – QA documents how closely SOPs followed

    • • Test and Control Article Characterizations
    • – To determine the strength (potency), purity, stability, & physicochemical properties of the potential drug molecule and control substances before major non clinical research is conducted (does not include determine structure of the drug molecule)
    • – Critical question: Will drug molecule be stable during non clinical study?
  22. TOXICOLOGY STUDIES (continued)
    • • The Protocol and Conduct of Non Clinical Studies
    • – Each study must have a written protocol (objectives & methods)
    • – Protocol must be approved by Study Director in advance of the study

    • • Records and Reporting
    • – A final report is required for each study (summary, methods, results, &conclusions)
    • – Reports must be properly stored in a secure repository (usually within the corporate Regulatory Department)

    • • Equipment Design
    • – Maintenance, calibration, standardization of equipment used in the studies must be documented
    • – Appropriate design & adequate capacity, suitably located within the GLP facility

    • Notes: FDA audits of GLP facilities on a regular basis will demonstrate compliance to 21 CFR Part 58
    • • Types of Non Clinical Tox Studies Required by FDA
    • – Acute (or 14 Day) Studies
    • – Subacute (or 90 Day) Studies
    • – Chronic (or 180 Day) Studies
    • – Carcinogenicity (“CARC”) Studies
    • – Genotoxicity/Mutagenicity Studies
    • – Special Tox Studies
    • – Reproductive Tox Studies

    • A complete set of data from the above studies is not required to initiate Phase I human clinical trials. However, sufficient non clinical tox data is required to convince FDA that the drug candidate will be reasonably tolerated by the first few humans administered the drug. Although certain safety data from tox studies prior to initiation of clinical studies is expected, precisely what non clinical tox data is required is dependent on discussions/negotiations between the sponsoring biopharmaceutical company and FDA.
  24. MTD
    Maximum Tolerated Dose-- Dose sufficiently high to observe minimal toxicity without seriously affecting animal’s life span. The MTD dosage will typically be one of the dosages for later Carcinogenicity Studies.
  25. NOAEL
    (No Observed Adverse Effect Level)-- In a series of dosages, the highest dose in which toxicity is not observed, but at the next higher dose, toxicity is seen. The NOAEL dosage of the same drug will vary with the drug regimen and the animal species.
    • The FDA expects carcinogenicity testing to be performed for drugs used continuously for 6 months or longer or for drugs used intermittently to treat chronic or recurrent diseases.

    • Objective: to assess the carcinogenic potential of certain new drug candidates.

    • • Methods (discuss with FDA before initiating)
    • – Species: rats and mice
    • – Route: same as expected for humans; more than one if not sure of human route
    • – Dosage level: MTD, multiple dosage levels
    • – Duration: 6 months to 2 years (rodent life span)
    • – Animals euthanized and evaluated for tumors
    • – Photosensitivity studies with UV irradiation for topicals and drugs known to concentrate in skin

    • Carcinogenicity studies do not typically begin until Phase II “Proof of Concept,” however if FDA has concerns about carcinogenic potential as a result of genotoxicity studies, may require earlier.
    • • Objectives
    • – To assess a drug candidate’s potential to cause genomic (DNA) damage thatcould cause cancer (somatic cell mutation) and/or heritable defects (germ cellmutation)

    • • When to Perform?
    • – Generally, in vitro testing (e.g., Ames test, cell culture based cytogenetic assessments) completed prior to first human exposure of drug
    • – Some in vivo testing (e.g., bone marrow, micronucleus tests) may run concurrently with clinical studies
    • – Discuss with FDA

    • • Types of Testing
    • – Bacterial mutation assays (Ames test)
    • – Tests for hemopoietic damage in animals
    • – Clastogenic (chromosome breakage) assessments
    • – Cell culture cytogenetic evaluations
    • – Micronucleus testing in rodents
    • – Gene array/gene chip systems have come to the fore in the last few years
    • Non standard toxicity testing that may be required by FDA for a particular drug class (e.g., certain nucleosides & nucleotides),formulation, disease, or targeted age group. Precedence indicates these types of drug may exert “unusual” toxicities, and therefore need more careful safety scrutiny before exposure to humans.

    • Discuss with FDA before initiating toxicology studies to supportthe IND
    • The FDA requires reproductive tox testing in animals for a drug candidateintended to be used in women of childbearing age, regardless of whetherthe target population is pregnant females. In the last several years, somereproductive tox studies relevant to male reproductive potential have alsobeen requested by the FDA.

    • Both women and men who participate in clinical studies are required to usesome form of conception control (except for those sterile or postmenopausal).

    • • Reproductive tox studies comprise 3 segments
    • Segment I
    • • Objective: to assess general reproductive performance
    • Segment II
    • • Objective: to determine teratologic potential
    • Segment III
    • • Objective: to evaluate perinatal (last 3rd of pregnancy) and post natal development through lactation and sexual maturity
    • 1st Priority: Animal Toxicology Data
    • – Survivors?
    • – Tissue pathologies?
    • – Special toxicologic observations?
    • – Reproductive toxicology?
    • – Other pharmacodynamic effects (e.g., abnormal labs)

    • 2nd Priority: ADME/PK Data
    • – Is an orally dosed drug systemically absorbed?– Systemic distribution?
    • – Adequate t½?
    • – Blood or tissue Cmax ≥ IC50?

    • 3rd Priority: Non Clinical Activities
    • – Potency?
    • – Cytotoxicity?
    • – Selectivity Index?
    • – Desired mechanism of action?
    • – Spectrum (broadness) of activity?
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Drug Development Process Lecture III
Drug Development
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