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NEW DRUG DEVELOPMENT PROCESS NEW CHEMICAL ENTITY SOURCES: Organic Synthesis Molecular Modification Isolation from plants Genetic Engineering
Biological
Pharmacology ADME
Toxicology
Preformulation
PRECLINICAL STUDIES (Continued) long term animal toxicity product formulation Manufacturing and controls Package and label design
Methods of Drug Discovery Although some drugs may be the result of fortuitous discovery, most of drugs are the result of carefully designed research programs of screening, molecular modification, and mechanism-based drug design
1. Random or untargeted screening involves the testing of large numbers of synthetic organic compounds or substances of natural origin for biologic activity
Purposes:
to detect an unknown activity of the test compound or substance to identify the most promising compounds to be studied by more sophisticated nonrandom or targeted screens to determine a specific activity
2. Molecular modification - is chemical alteration of a known and previously characterized organic compound (frequently a lead compound) for the purpose of enhancing its useful as a drug
PURPOSES: 1. Enhance its specificity for a particular body target site 2. Increasing its potency 3. Improving its rate and extent of absorption 4. Modifying the advantage its time-course in the body 5. Reducing its toxicity 6. Changing its physical and chemical properties
PURPOSE:
The intention is the interaction of the drug with specific cell receptors, enzymes systems, or metabolic process of pathogens or tumor cells, resulting in blocking, disruption, or reversal of the disease process
2. Ranitidine - Zantac - an inhibitor of histamine at the histamine H2receptors, including receptors on the gastric cells. Used to treat gastric ulcers 3. Sertraline - Zoloft - which inhibits the central nervous systems neuronal uptake of serotonin, making the drug useful in the treatment of depression.
Lead compound
-is a prototype chemical compound which has a fundamental desired biologic or pharmacologic activity.
3. Most drugs exhibit activities secondary to their primary pharmacologic action. Example: Finasteride -Proscar was originally developed and approved to treat benign prostatic hyperplasia. Later, the same drug Propecia was approved at lower recommended dosage to treat male pattern baldness
Prodrugs
-is a term used to described a compound that requires metabolic biotransformation following administration to yield the desired pharmacologically active compound.
Example of Prodrug
Enapril maleate Vasotec -which, after oral administration, bioactivated by hydrolysis to enaprilat, an ACE inhibitor used in the treatment of hypertension
Prodrug may be design preferentially for solubility, absorption, biostability and prolonged release
Solubility - Enabling the use of specifically desired dosage forms and routes of administration Absorption - A drug may be made more water or lipid soluble, as desired, to facilitate absorption via the intended route of administration
Biostability - An active drug is prematurely destroyed by biochemical or enzymatic process, the design of a prodrug may protect the drug during its transport in the body Prolonged Release - Depending on a prodrugs rate of metabolic conversion to active drug, it may provide prolonged release and extended therapeutic activity
A combination of two or more old drugs or a change in the usual proportions of drugs in an established combination product is considered new if the change introduces a question of safety or efficacy.
- A new dosage schedule or regimen, a new rout of administration, new dosage form all cause a drug or drug products status to new and triggers reconsideration for safety and efficacy - A drug need not be a new chemical entity to be considered new. A change in a previously approved drug products formulation or method of manufacture constitutes newness under the law, since such changes can alter the therapeutic efficacy and/or safety of a product.
NOMENCLATURE OR NAMING OF DRUG The task of designating appropriate non-proprietary names for newly found chemical agents rests primarily with the USAN Council. The official name for a drug is referred to as the drug nonproprietary or public name
in contrast to the proprietary or brand names or trademark names given by the specific manufacturers or distributors of the drug.
The term generic name, has been used extensively in referring to the nonproprietary names of the drugs. Brand name is registered as a trademark with the United States Patent Office
CATEGORY OR USE In general, drugs exert their effects by one of three means: 1. By exerting a physical action such as the protective effects of ointments and lotions upon topical application
2. By reacting chemically outside the body cells. Example: antacids counteract excess acidity in the stomach or antibiotics to act against invading pathogenic microorganism.
3. By modifying the metabolic activity of the bodys cell. Majority of the drugs belong to the 3rd manner where brain, liver, kidney, etc. are affected
Proposals for Nonproprietary Names 1. Be short and distinctive in sound and spelling and not be such that it is easily confused with existing names
2.Indicate the general pharmacologic or therapeutic class into which the substance falls or the general chemical nature of the substance if the latter is associated with the specific pharmacologic activity 3. Embody the syllable or syllables characteristic of a related group of compounds
Pharmacology
pharmaco= drugs; logos = study of; is the science concerned with drugs, their sources, appearance, chemistry, actions, and uses.
The term can be expanded to include 1. Properties 2. Biological and physiologic effects 3. Mechanism of actions 4. ADME
Pharmacodynamics = the study of the biochemical and physiologic effects of drugs and their mechanism of action
Pharmacokinetics = ADME
Clinical Pharmacology = applies pharmacologic principles to the study of the effects and actions of drugs in humans
Pharmacologic profile = In vitro cultures of cells and enzymes systems and in vivo animal models are used to define a chemicals pharmacologic profile = Most animal testing is done on small animals, usually rodents (mouse, rats) for a number of reasons including cost, availability, the small amount of drug required for a study,
the ease of administration by various routes (oral, inhalation, intravenous) and experience with drug testing in these species
Animal models: dog or rat for hypertension; dog and guinea pig - for respiratory effects; dogfor diuretic activity; rabbit - for blood coagulation; mouse and rats - for CNS studies
Drug Metabolism
1. The extent and rate of drug absorption from various routes of administration, including the one intended for human use
2. The rate of distribution of the drug through the body and the site or sites and duration of the drugs residence
3.The rate, primary and secondary sites, and mechanism of the drugs metabolism in the body and the chemistry and pharmacology of any metabolites 4. The proportion of administered dose eliminated from the body and its rate and route of elimination
Toxicology
Deals with the adverse or undesired effects of drugs Not all side effects of new drugs to be tested in animals will be detected but the greater the likelihood the effect will also be seen in humans Example: headache
Purpose of Safety Evaluation and Toxicity Studies 1.The substances potential for toxicity with short-term (acute effects) or long- term use (chronic effects) 2.The substances potential for specific organ toxicity 3.The mode, site, and degree of toxicity
4.Dose-response relationships for low, high, and intermediate doses over a specified time
5.Gender, reproductive, or teratogenic toxicities 6. The substances carcinogenic and genotoxic potential
Acute or Short-Term Toxicity Studies These studies are designed to determine the toxic effects of a test compound when administered in a single dose and/or in multiple dose doses over a short period, usually a single day.
Animals are observed: eating and drinking habits; weight changes; toxic effects; psychomotor changes; feces and urine are collected. Animal death: recorded; study on histology; pathology and statistically evaluated on the basis of dose response
If the drug is to be used for a chronic human illness, animal studies 1 year or longer must be undertaken to support human use. Compare the strain, sex, age, dose levels and ranges, routes of administration, duration of treatment, observed effects, mortality, body weight changes, food and water consumption,
physical examination (electrocardiography, ophthalmic, examination), hematology, clinical chemistry, organ weights, gross pathology, neoplastic pathology, histopathology, urinalysis, ADME data
Carcinogenicity Studies
Usually component of chronic testing and is undertaken when compound has shown sufficient promise as a drug to enter human clinical trials. Carcinogenicity studies are long term (18-24 months), with surviving animals killed and studied at defined weeks during the test period
Data on the causes of animal death, tumor incidence, type and site, and necropsy findings are collected and evaluated Preneoplastic lesions and/or tissue-specific proliferation effects are important findings
Reproduction Studies
Reproduction studies are undertaken to reveal any effect of an active ingredient on mammalian reproduction
Included in these studies are fertility and mating behavior; early embryonic, prenatal, and postnatal development, multigenerational effects, teratology
In these studies, the maternal parent, fetus, neonates, and weaning offspring are evaluated for anatomic abnormalities, growth, and development. The animal used in other toxicity studies in reproductive studies, usually the rats.
In embryotoxicity studies only, a second mammalian species traditionally has been required. The rabbit is the preferred choice for practically and the extensive background knowledge accumulated on this species.
- This is the area of responsibility of pharmaceutical scientists and formulation pharmacists trained in pharmaceutics
Preformulation Studies
- Each drug substance has intrinsic chemical and physical characteristic that must be considered before the development of a pharmaceutical formulation
- Among these are the drugs solubility, partition coefficient, dissolution rate, physical form, and stability
Drug Solubility
- A drug substance administered by any route must posses some aqueous solubility for systemic absorption and therapeutic response
- Poorly soluble compounds (example less than 10mg per ml aqueous solubility) may exhibit incomplete, erratic, and or slow absorption and thus produce a minimal response at desired dosage
Partition Coefficient -A drug partition coefficient is a measure of its distribution in a lipophilichydrophilic phase system and indicates its ability to penetrate biologic multiphase system Dissolution Rate
Physical Form
-The crystal or amorphous forms and or the particle size of a powdered drug can affect the dissolution rate, thus the rate and extent of absorption, for a number of drugs
Initial Product Formulation and Clinical Trial Materials - Prepared for Phase 1 and Phase 2 for clinical trials - Phase 1 studies, for orally administered drugs, capsules are employed containing the active ingredient alone, without pharmaceutical excipients
-Phase 2, the final dosage form is selected and developed for Phase 3 trials, this is the formulation that is submitted to the FDA for marketing approval
Blinded Studies
-Are controlled studies in which at least one of the parties (example, patient, physician) does not know which product is being administered
= Some studies are open label, in which case all parties may know what products are administered
In all clinical study programs, the package label of the investigational drug must bear the statement Caution: new drug limited by federal ( or United States) law to investigational use
Submission
FDA Review Pre-approval Plant inspection FDA action
IND
5. Analytical method
6. Pharmacology
7. Toxicology 8. Efficacy in animals
Investigational new drug (IND) submission -the rationale for the drug and patient group to be treated -all pre clinical safety and efficacy data -detailed plan for clinical development -CIB( clinical investigators brochure)
Ethics
Declaration of Helsinki-1964 The clinical trial must minimize the risk for participants Provision for care of the patients Terminate the trial when the risk becomes incompatible with the goals of the trial Adverse events to be reported immediately to an ethical committee
Ethics Committees
The ethics committee reviews a protocol before the study is allowed to start. Their job is to ensure that the risks of being in the study are not greater than the potential benefit.
To ensure the rights and welfare of the participants FDA regulations mandates to review the clinical trial protocols for ethical and legal issues Also has the authority to approve, modify or disapprove it
Informed Consent
69
Informed Consent
70
Clinical
trials have a long history even if not acknowledged as Clinical trials record of clinical trials dates back to the time of the Trialists:
Formal
Dr. Van Helmonts proposal for a therapeutic trial of bloodletting for fevers [1628] Dr. Linds, a ship surgeon, trial of oranges & limes for scurvy [1747]
NY/VI AETC
Review
of scientific background
Written
tested
hypothesis/hypotheses to be
Study
design -type -study population PROTOCOL -statistical analysis -enrollment of subjects -intervention -follow up of subjects Organization
A A
A A
A A
Phase III: Effectiveness compared to standard of care; Safety (More than 100 to a few thousand)
A
A A
A A
A A
A A
A A
A A
75
Phase 0
Recent designation as per FDA-2006 guidelines First in humans 100th of the pharmacological dose Early PK and PD data Minimal pre clinical study Adv : unreliable in vitro and animal study Disadv : safety/efficacy
Phase 1
Participants (fewer than 100 healthy people) Dose Determines safety of the drug Involve dose ranging studies to determine toxicity and major adverse effects
Phase 2
Phase 2A
Pilot study Dose defining and dose form Safety and efficacy PK/PD data Risk benefit ratio
Phase 2B
Phase 3
No fixed time and population purpose is usually to support the marketing campaign Rare ADRs Drug interaction New clinical indication (Phase 5)
The
Some clinical trials have been critical to patient health & provision of health care For instance:
Protocol 076: HIV perinatal transmission 1st trial of AZT o Various cancer treatments o Development of other HIV related medications like PIs
o
Medications did not work as in pre clinical study Loss of Follow-Up Harmful substance Unethical & poorly conducted study (Ex: Gene Replacement Study)
APPROVAL
Once all clinical data has been submitted, reviewed and approval is granted to license in market Post marketing surveillance Approval takes 6 months to 2 years
Name and title of the person responsible for monitoring the conduct and progress of the investigation
Names and titles of the persons responsible for the review and evaluation of information relevant to the safety of the drug Name and address of any contract research organization involved in the study Identification of the phase or phases of the clinical investigation to be conducted
If the new drug is a combination of previously investigated components, a complete preclinical summary of these components when administered singly and any data or expectations relating to the effect when combined Clinical protocol for each planned study Commitment that an Institutional Review Board has approved the clinical study and will continue to review and monitor the investigation
Investigator brochure
Commitment not to begin clinical investigations until the IND is in effect, the signature of the sponsor or authorized representative, and the date of the signed application
Clinical Protocol As a part of IND application, clinical protocol must be submitted to ensure the appropriate design and conduct of the investigation Clinical Protocol include: Statement of the purpose and objectives of the study Outline of the investigational plan and study design
Estimate of the number of patients to be involved Basis for subject selection, with inclusion and exclusion criteria Description of the dosing plan, including dose levels, route of administration, and duration of patient exposure Description of the patient observations, measurements, and tests to be used
Clinical procedures, laboratory tests, and monitoring to be used in minimizing patient risk
Type 1 New Molecular entity, not marketed in US Type 2 New ester, new salt, or other derivative of an approved active moiety Type 3 New formulation of a drug marketed in US
Type 4 New combination of two or more compounds Type 5 New manufacturer of a drug marketed in US Type 6 New therapeutic indication for an approved drug
By Therapeutic Classification Type P Priority review, a therapeutic gain Type S Standard review, similar to other approved drugs
Additional Classification Type AA For treatment of AIDS or HIV-related disease Type E For life-threatening or severely debilitating disease Type F Review deferred pending data validation
Drug Dosage and Terminology The safe and effective dose of a drug depends on different FACTOR: 1.Characteristics of the drug substance
Usual adult dose - the amount of drug that will produce the desired effect in most adult patients.
Usual Dosage range - indicates the quantitative range or amounts of the drug that may be prescribed safely within the framework of usual medical practice.
MTD Median Toxic Dose - is the amount that will produce a defined toxic effect in 50% of the individuals tested
The relationship between the desired and undesired effects of a drug is commonly expressed as the Therapeutic index and is defined as the ratio between a drugs median toxic dose and its median effective dose, TD50/ED50.
Some factors of patients considered in determining a drugs dose in clinical investigations and in medical practice include the following: Age
Body Weight
Body Surface Area Sex Pathologic State Tolerance
Morphine
Phenytoin Quinidine Theophylline
0.1
5-22 3-6 20-100
-50 10 --
0.05-4
100 30-50 --
Less Than 5
Between 5 and 10
Greater Than 10
Amitriptyline
Barbiturates Bromide
Acetaminophen
Methadone
Procainamide Quinidine
Paraldehyde
Primidone Thioridazine
Nortriptyline
Pentazocine Propoxyphene
mouth
sublingual
parenteral intravenous intraarterial
TERM
SITE
intracardiac heart intraspinal/intrathecal spine intraosseous bone intraarticular joint intrasynovial joint-fluid area intracutaneous/intradermal skin subcutaneous beneath the skin intramuscular muscle
TERM
SITE
conjunctival
conjunctiva
TERM
SITE
6.Precautions
7.Adverse reactions
8.Drug abuse and Dependence 9.Over dosage
Some products, however, have been approved and later removed from the market for safety reasons, including the following: Grepafloxacin HCL (Raxar) Brofenac sodium (Duract) Cisapride (Propulsid) Alosetron HCL (Lotrovec) Fenfluramine HCL (Pondimin)
Dexfenfluramine HCL (Redux) Terfenadine (Seldane) Cerivastatin (Baycol) Mibefradil (Posicor) Astemizole (Hismanal) Troglitazone (Rezulin)
Clinical
NDA Review Post Marketing Research and Surveillance Development Adverse reaction
Phase 1
Phase 2
Animal testing
Short term
Long term
Inspection
Average 7 years
NDA submitted
NDA approval
New pharmacologic categories of drugs including oral hypoglycemic drugs effective against certain types of diabetes mellitus - Antineoplastic or anticancer drugs,
- Immunosuppressive agents to assist the bodys acceptance of organ transplant - Contraceptives to prevent pregnancy - Tranquilizers and antidepressant drugs to treat the emotionally distressed
8. Moxifloxacin HCl - Avelox - infectious disease 9. Montelukast sodium - Singulair - chronic asthma 10. Tegaserod maleate - Zelnorm - irritable bowel syndrome in women 11. Sodium oxybate -Xyrem - cataplexy in patient with narcolepsy 12. Galantamine HCl - Reminyl - dementia with Alzheimers disease 13. Fondaparinux sodium - Arixtra - deep vein thrombosis 14. Voriconazole - Vfend - infectious disease