DRUG DISCOVERY AND DEVELOPMENT

Drug discovery and development process aims to make available medications that are safe and
effective in improving the length and quality of life and relieving pain and suffering. However, the
process is very complex, time consuming, and resource intensive, requiring multi-disciplinary expertise
and innovative approaches.

Recent estimates suggest that it takes up to 13.5 years and 1.8 billion U.S. dollars to bring a new drug
to the market. There is a growing urgency to identify and develop more effective, efficient, and
expedient ways to bring safe and effective products to the market. The drug discovery and
developmental process relies on utilizing relevant and robust tools, methods, and models that are
predictive of clinical effects in terms of diagnosis, prevention, therapy, and prognosis. There is a
growing emphasis on translational research, a bidirectional bench to the bedside approach. The all-
important predictivity depends on having robust, relevant, validated and qualified biomarkers for
physiological and pathological effects of interest.

Medicinal chemistry and pharmaceutics play a crucial role from the beginning of the drug discovery
and development process, involving chemical synthesis (including compliance with current Good
Manufacturing Practice, cGMP), characterization, purification, chemical alteration, stability
determination, and formulation of the drug candidate

Medicinal Chemistry
- relates to the design and production of compounds that can be used in medicine for the prevention,
treatment or cure of human and animal diseases.

Medicinal chemistry covers three critical steps:

1. A discovery step: consisting of the identification and production of new active substances usually
called lead compounds. Leads can originate from synthetic organic chemistry, from natural sources or
from biotechnological processes.

2. An optimization step: that deals mainly with the synthetic modification of the lead structure in order
to improve potency, selectivity and lessen toxicity. Its characteristics are the establishment and
analysis of structure' -activity relationships (SARs). 3. A development step consisting of the
optimization of the synthetic route for bulk production. Modification of the pharmacokinetic and
pharmaceutical properties of the active substance to render it suitable for clinical use.

This may cover optimization of properties associated with:

 Chemical formulation
 Solubility
 Elimination of unpleasant taste or irritation
 Reduction of pain at site of injection

DRUGS CAN BE CLASSIFIED UNDER THE FOLLOWING CATEGORIES:

1. The origin of the drug
a. Minerals: iodine, phosphates, calcium, sodium , iron
b. Animal kingdom: insulin, fish oils, biliary salts
c. Vegetable or plant origin: alkaloids, cardiac glycosides, anticancer agents
d. Genetic engineering and fermentation products

2. The mode of Action

 Medicine that treat the cause of the disease termed "true drugs" or etiological drugs.
Antibacterials, antifungals, antivirals and antiparasitics (chemotherapeutic drugs). Activity resides
in their selective toxicity or the ability to destroy the invader without destroying the host. This
includes also vaccines and preventive therapies.
3. The nature of illness
 The world health organization (WHO) in 1968 adopted this physiological classification which
classifies drugs by the body system on which they act.
EX. Cardiovascular, Diuretics, immunomodulators

4. The chemical structure

Disease has been recognized as an enemy of humankind since civilization began, and plagues of
infectious diseases arrived as soon as humans began to congregate in settlements about 5000 years
ago. Early writings on papyrus and clay tablets describe many kinds of disease, and list a wide variety of
herbal and other remedies used to treat them. The earliest such document, the famous Ebers papyrus,
dating from around issoBC, describes more than 80o such remedies. Disease was in those times
regarded as an affliction sent by the gods; consequently, the remedies were aimed partly at
neutralizing or purging the affliction, and partly at appeasing the deities. Despite its essentially theistic
basis, early medicine nevertheless discovered, through empiricism and common sense, many plant
extracts whose pharmacological properties we recognize and still use today; their active principles
include opium alkaloids, ephedrine, emetine, cannabis, senna and many others

The present medicinal system is dominated by the Allopathy or western medicine which is prominently
taught and practiced in most of the countries world wide. This system is still evolving and during last
few decades focus was based on chemical origin of most of the medicines. Thus majority of drugs in
current practice are from synthetic origin.

Ayurveda, one of the oldest systems used by mankind for well being (Sharma 1995), originated in
ancient India many thousand years ago (about 4500 BC as agreed by most scientists).

Ayurveda literally means "science of life" in Sanskrit (Ayur: Life; Veda: Science). It is not only a medical
system but a way of life. Ayurveda aims at a holistic management of health and diseases. It is widely
practiced in the Indian subcontinent and is also one of the official systems of medicine in India. Its
concepts and approaches are considered to have been perfected between z5oo-5oo BC.

Charak Samhita and Sushrut Samhita (loo-soo BC) are the two main Ayurvedic classics, wherein more
than no plants along with their classification, pharmacological and therapeutic properties have been
described.

It is divided into eight major disciplines known as Ashtanga Ayurveda.

1. Kaaya Chikitsa (Internal Medicine)

2. Baala Chikitsa (Treatment of Children / Pediatrics)
3. Graha Chikitsa (Demonology / Psychology)
4. Urdhvaanga Chikitsa (Treatment of disease above the clavicle)
5. Shalya Chikitsa (Surgery)
6. Damstra Chikitsa (Toxicology)
7. Jara Chikitsa (Geriatrics, Rejuvenation)
8. Vrsha Chikitsa (Aphrodisiac therapy)

Kaya Chikitsa (Internal Medicine)

The word 'Kaya' represents 'Agni'—the digestive fire in the body. The discipline of Kaya Chikitsa deals
with the treatment of general ailments, like fever, diarrhea, cough, skin disorders, lung diseases, and
bone disorders, by bringing Agni back in balance.

Baala Chikitsa (Pediatrics)

Bala Chikitsa is the pediatric offshoot of Ayurvedic science for healing that details disorders,
treatments, and dietary recommendations, natural and herbal remedies for various diseases
concerning children and infants such as digestive disorders, teething problems, bone health, and
nutritional requirements, among others. In covering the overlapping subjects of gynecology and
pediatrics, it also discusses the art of nursing, infertility, mental health of the mother and its influence
on the infant's well-being.

Graha Chikitsa (Psychology)

Graha Chikitsa is the psychic field of Ayurveda that deals with diseases and illnesses of the mind or
diseases with psychosomatic roots. Psychosomatic disorders are ones that do not have visible
symptoms but are rooted in factors related to mental health. This field talks about herbs and their
applications as disinfectants and their abilities to bring positivity in the atmosphere. It talks about
herbs, diet, use of specific mantras, pranayama or breathing techniques, meditation techniques and
yogic therapies for healing the mind.

Urdhvaanga or Shalakya Chikitsa (EENT)

Shalakya Tantra deals with treating diseases and imbalances in body parts above the shoulders through
holistic treatments, cleanses and herbal formulations. Shalakya Tantra is the EENT
(otorhinolaryngology) and ophthalmology field equivalent of Ayurveda that deals with conditions of
the eyes, ears, nose, lips, brain, central nervous system, skull and throat. This field is further divided
into Nethrachiktsa (ophthalmology), Karnachikitsa (otology), Nasachikitsa (rhinology),
Mukharogachikitsa (includes dentistry and laryngology), and Shirorogachikitsa (craniology).

Shalya Chikitsa (Surgery)

Shalya Tantra details pre-operative procedures, post-operative procedures, general procedures, energy
points (marmas), and even anesthesia procedures along with the right type of instruments to use,
bandages, or sutures to be used for the specific procedures. Most of these instruments were made of
stone, wood, bark, or thick leaves.

Damstra Chikitsa (Toxicology) Damstra Chikitsa or Agada Tantra is the branch of toxicology in
Ayurveda that deals with treatments and prevention of toxins in the body. It dealt with poisoning from
animals, plants, vegetables, or metals or man-made poison. But more importantly, this branch of
Ayurveda also considered air and water pollution as a form of poisoning that needed to be purified for
health and well-being of man, as contamination would often lead to mass scale epidemics. Ayurveda
accords as much importance to purity of air, water, earth, and space as much as to the food,
environment and quality of life.

Rasayan/Jara Chikitsa (Geriatrics & Rejuvenation)

This branch of Ayurveda deals with diseases and illnesses related to aging, as well as science of
longevity and rejuvenation. It deals with preventive healthcare. tips. treatments, herbal medicines
(rasayana) to enhance quality of life and lead a healthy. happy life full of vitality and vibrancy. Jara
chikitsa (jara meaning degeneration) also deals with degenerative disorders irrespective of ones age.
This Ayurveda branch talks about different types of rasayanas like Ausadha Rasayana (drug based),
Ahara Rasayana (dietary), and Achara Rasayana (behavioral discipline). Jara Chikitsa includes healing
modalities to achieve longevity, better memory, youthfulness, brightness. positive emotions and
virtues, strength, immunity and vitality. Rasayana works to improve dosha imbalances, rekindle
digestive Agni and restore health with use Of diet and herbal medication. Three sub branches of
Rasayana Chikita—Nainuttika Rasayana (curative rejuvenation). Ajasrika Rasayana (promotion of
health and a healthy lifestyle) and Kamya Rasayana (longevity, fertility and memory enhancement).
Naimittika Rasayana is a curative discipline that examines and uses herbal drugs, formulations and
their potency to speed up recovery from existing diseases or illnesses. Ajasrika Rasayana is dedicated
to the science of wellness and includes everything from diet, herbs, dairy, exercise and practices to
lead a spiritually, mentally and physically optimal life. It details the goodness and benefits of everything
that the nature provides for enhancing human health. Kamya Rasayana is the discipline that deals with
the biochemistry of desire (kama), it also talks about the science of prang or life force, memory and
intellect and how these can be improved along with increasing lifespan.

Vrsha or Viijikarana Chikitsa (Aphrodisiac Therapy)

This branch deals with promotion of sexual health of men and women and improvement in fertility. It
focuses on the health and illnesses of reproductive or genetic organs. It is a branch that talks about sex,
virility, potency, strength, excitability, techniques, regimen, diet, herbal medicines, and treatments to
take care of reproductive organs, and diseases such as sexual dysfunctions, infertility, premature
ejaculation, and erectile dysfunction. The herbs and medicines administered under the Vajikarna
sciences have qualitative and quantitative properties. For example, to increase sperm count, medicines
called Sukrala are recommended that include Mvagandha Musa, Sarkara, Satavart; to improve
ejaculation ingredients called SukraRecaka are administered that include milk, specific type of meats,
fruit pulps or amalaki; fruits like jatiphala constitute SukraStambhaka medicines that help in increasing
the time of intercourse; and Sukrasosaka herbs like haritaki are the ones that help control excessive
semen production.

DRUG SAFETY EVALUATION

What is Drug Safety Evaluation?

All medicinal products carry risks in addition to their possible benefits. For developing a new medicine,
a decision can only be made if both benefits & risks are addressed. Risk associated with the drug is
minimized when medicines of good quality, safety & efficacy are used rationally by an informed health
professional & by patients. Guidelines were developed to monitor drugs, foods & environmental
contaminants for adverse reactions & toxicity. Pharmacovigilance helps in reducing the risk of harm by
ensuring use of good quality medicines approprietely.

In beginning, guidelines were restricted to local needs. In clinical trilas, critical efficacy endpoints are
identifies in advance & sample sizes are estimated for assessment of effectiveness.

DRUG SAFETY EVALUATION (TOXICITY STUDIES)

INTRODUCTION

In biology, the term "in situ" means that the examination and observation of a rare occurrence take
place where it occurs. Subjects are examined on position and are not moved to another or channel. An
example is an observation of dolphins at sea. they observed where they are found and are not moved
to an aquarium or other container which is more convenient. In cell science, in situ can mean
something
in between in vivo and in vitro.

IN VIVO
 "in vivo" is a latin word which means "within the living."
 it is the experiment or observations done on the living tissue of the whole living organism in a
controlled environment.
 in vivo experiments are done in the organism's natural environment or in the organism itself.
 precise cellular conditions are presented in these studies.
one example is a clinical testing or a clinical trial which can be controlled testing of a new drug
or device on human subjects. the subjects are given the drugs and are observed for a certain
period of time
 another is animal testing which is an experiment that is done in animals usually rats, birds, frogs,
and other animals where the drugs are directly injected into the body. so in vivo experimetnts,
conditions are not manipualted or controlled.
 it is found to be more suited on experiments done on organisms that are alive
 in medicine, clinical trials and animal testing are performed in vivo to analyze the overall effects of
the experiments.
 in vivo experiments, living cells, or animal models are used. in vivo studies are crucial for the
development of medical devices, surgical instruments, rocedures and novel therapeutics.

IN VITRO

 "in vivo" is a latin word that means "within the glass." therefore the studies which are done
outside the living organism,inside glass (test tubes or petrishishes) are known as in vitro studies.
 it is the experiment or observations done on the tissue outside of the living organism in a
controlled environment, usually using petri dishes and test tubes.
 the term in vitro is used in cell biology to explain the techniques which are performed on a
controlled environment outside a living cell or organism
 most experiments in cellular biology are done through in vitro studies and are not conducted in
the organism's natural environment. this results in the limited success of the experiments in
simulating the actual conditions inside an organism and make its outcome less precise.
 compared to in vivo experiments, it is less epensive and provides quicker results.
 most of the cellular, biochemical experiments are carried out in vitro in the labs to test.
 in vitro methods are widely used in the pharmaceutical industry to produce large scale
pharmaceuticals using microorganisms due to its ease of production and economic benefits.

"Methods and principles underlying various toxicological tests.”

CURRENT METHODS: GENERAL CONSIDERATIONS

 Toxicity studies are required to assess potential hazards to humans through the acute, subchronic,
and chronic exposure of laboratory animals to pesticides. The more specific types of toxicity that
are determined include carcinogenicity; developmental (including teratogenicity in offspring) and
reproductive toxicity; mutagenicity; and neurotoxicity

 Detailed information on the metabolism or biotransformation of the pesticide is also obtained.

Consideration is given to testing individual metabolites in animals, and in or on pesticide-treated
plants to which humans could exposed through their diet. The extent of metabolite testing
required depends on the level of potential toxicity and environmental persistence of the
metabolite. With the exception of the acute toxicity tests, most tests are conducted to determine
the nature of any toxicity that can be produced by repeatedly dosing animals over an extended
period. The results enable toxicologists to estimate the safety of a material of humans

Weil (1972) published the following set of guidelines, which reflected a consensus among toxicologists.
These should be considered before initiating a toxicity test:

1. Use, wherever practical or possible, one or more species that biologically handle the material
qualitatively and/or quantitatively as similarly as possible to man. For this, metabolism, absorption,
excretion, storage and other physiological effects might be considered.

2. Where practical, use several dose levels on the principle that all types of toxicologic and
pharmacologic actions in man and animals are dose-related. The only exception to this should be the
use of a single, maximum dosage level if the material is relatively nontoxic.
3. Effects produced at higher dose levels (within the practical limits discussed in 2) are useful for
delineating the mechanism of action, but for any material effect, some dose level exists for man or
animal below which this adverse effect will not appear.

4. Statistical tests for significance are valid only on the experimental units that have been
mathematically randomized among the dosed and concurrent control groups.

6. Effects obtained by one route of administration to test animals are not a priori applicable to effects
by another route of administration to man. The routes chosen for administration to test animals should,
therefore, be the same as those to which man will be exposed. Thus, for example, food additives for
man should be tested by admixture of the material in the diet of animals.

SUBCHRONIC TOXICITY STUDIES

 Most subchronic toxicity studies monitor clinical or behavioral (neurological) signs of toxicity, body
weight, food consumption, eye effects, certain plasma or serum and urine parameters, organ
weights, and gross and microscopic pathology. Clinical and behavioral signs of toxicity are
observed and recorded daily. They can consist of activity, gait, excreta, hair coat, and feeding and
drinking patterns. Body weight and food consumption data are routinely recorded throughout the
study at intervals (usually weekly) determined by the length of the study. Ophthalmoscopic
examinations are conducted at the beginning of the study and, typically, just before it terminates.

CHRONIC TOXICITY STUDIES

 Information derived from chronic studies is used to assess potential hazards resulting from
prolonged and repeated exposure to a pesticide over a large portion of the human life span. These
studies usually last 12 to 24 months. Of particular importance are long- term carcinogenicity
studies, the purpose of which is to observe the test animals for the development of neoplastic
lesions after a lifetime of exposure at dose levels up to and including the MTD determined from
subchronic testing.

 The emphasis of the carcinogenicity study is the detection of tumors in animals. For these studies,
both concurrent and historical control data are used to evaluate the relevance of tumors.
Historical control data should be derived from studies in the same species and strain and,
preferably, in the same laboratory as used in the study under consideration.

DEVELOPMENTAL TOXICITY STUDIES

 Developmental toxicity studies are designed to assess the potential of developmental effects in
offspring resulting from the mother's exposure to the test substance during pregnancy. These
effects include death of the developing organism, structural abnormalities, altered growth, and
functional deficiencies. In addition to the classic teratology (now called developmental toxicity)
study, a postnatal study is required by the EPA on a case-by-case basis. It is in this study that
functional deficiencies are best studied.

 The EPA prefers that the rat and the rabbit be used in these studies; however, hamster and mouse
are also acceptable. Doses should be administered over the period of major organogenesis (major
visceral and skeletal formation) in the fetus. The maternal animals only are dosed in this study and
only for specified periods. When day 0 is the day that evidence of mating was observed, the rat
and mouse are dosed on days 6 through 15; the rabbit, days 6 through 18; and the hamster, days 6
through 14.
Drug Discovery and
Development as a
Process

ABELLA
ABING

ALIMODEN
AMAN
ARSENAL
Table
Table of
of Content
Content
Overview & Definition
Phases Stages
Step 1: Discovery & Development
Step 2: Preclinical Research
Step 3: Clinical Development
Step 4: FDA Review
Step 5: Post-market Monitoring
Other Relevant Drug Development
Concepts
Overview & Definition
The complexity in drug development has
increased manifolds over the past 40 years,
requiring preclinical testing, investigational new
drug (IND) applications, and completed clinical
testing before marketing approval from the FDA.
Generally, new drug applications (NDAs) or
biologics license applications (BLA) are
reviewed comprehensively before approval, and
then drug performance is resubmitted to
regulatory agencies for post-marketing studies.
The overarching goal is to bring more efficient
and safer treatments to the patients as quickly
as possible after a thorough medical
evaluation.
DRUG DISCOVERY & DEVELOPMENT
Drug discovery is a process which aims at identifying a compound therapeutically useful in
curing and treating disease. This process involves the identification of candidates, synthesis,
characterization, validation, optimization, screening and assays for therapeutic efficacy. Once a
compound has shown its significance in these investigations, it will initiate the process of drug
development earlier to clinical trials.
New drug development process must continue through several stages in order to make a
medicine that is safe, effective, and has approved all regulatory requirements. The process is
sufficiently long, complex, and expensive so that many biological targets must be considered for
every new medicine ultimately approved for clinical use and new research tools may be needed
to investigate each new target. From initial discovery to a marketable medicine is a long,
challenging task. It takes about 12 - 15 years from discovery to the approved medicine and
requires an investment of about US $1 billion. On an average, a million molecules screened but
only a single is explored in late stage clinical trials and is finally made obtainable for patients.
 Phases Stages
Phases Stages

Step 1:
Discovery and Development
Step 2:
Preclinical Research
Step 3:
Clinical Development
Step 4:
FDA Review
There are five critical steps in the U.S. Step 5:
drug development process, including FDA Post-market Safety
many phases and stages within each of
Monitoring.
them.

Step 1: Discovery & Development

 Drug discovery is how new medications are discovered. Historically, drugs
were mostly found by identifying active ingredients from traditional medicines
or purely by chance. Afterward, classical pharmacology was used to investigate
chemical libraries including small molecules, natural products, or plant extracts,
and find those with therapeutic effects. Since human DNA was sequenced,
reverse pharmacology has found remedies to existing diseases through testing.
Disease processes, molecular compound tests, existing treatments with
unanticipated effects, and new technologies spur drug discovery through the
cycle below.
Today drug discovery involves screening hits, medicinal chemistry, and
optimization of hits to reduce potential drug side effects (increasing affinity and
selectivity). Efficacy or potency, metabolic stability (half-life), and oral
bioavailability are also improved in this step of the drug development process.
Target Identification &
Validation

Target identification finds a gene or protein (therapeutic agent) that plays a

significant role in disease. When identified, therapeutic characteristics are
recorded. Targets are efficacious, safe, usable as drugs, and capable of
meeting clinical and commercial requirements. Researchers use disease
association, bioactive molecules, cell-based models, protein interactions,
signaling pathways analysis, and functional analysis of genes to validate
targets, or in vitro genetic manipulation, antibodies, and chemical genomics.
The Sanger Whole Genome CRISPER library and Duolink PLA are excellent
sources for drug discovery targets.
Hit Discovery Process
Following target validation, compound screening
assays are developed.

Assay Development & Screening

Assays are test systems that evaluate the effects of the

new drug candidate at the cellular, molecular, and
biochemical levels.
 High Throughput
Screening

High Throughput Screening (HTS) uses robotics, data processing/control

software, liquid handling devices, and sensitive detectors to rapidly conduct
millions of pharmacological, chemical, and genetic tests, eliminating hours of
painstaking testing by scientists. HTS identifies active compounds, genes, or
antibodies that affect human molecules.

Hit to Lead

In the Hit to Lead (H2L) process, small molecule hits from an HTS are evaluated
and optimized in a limited way into lead compounds. These compounds then
move on to the lead optimization process.
Lead Optimization

In the lead optimization (LO) process, the lead compounds discovered in the
H2L process are synthesized and modified to improve potency and reduce
side effects. Lead optimization conducts experimental testing using animal
efficacy models and ADMET tools, designing the drug candidate.

Active Pharmaceutical Ingredients

Active pharmaceutical ingredients (APIs) are biologically active ingredients in a drug

candidate that produce effects. All drugs are made up of the API or APIs and
excipients. (Excipients are inactive substances that deliver the drug into the human
system.). High Potency Active Pharmaceutical Ingredients (HP APIs) are molecules
that are effective at much smaller dosage levels than standard APIs. They are
classified based on toxicity, pharmacological potency, and occupational exposure
limits (OELs), and used in complex drug development involving more than ten steps.

The drug discovery process ends when one lead compound is found for a drug
candidate, and the process of drug development starts.
 Step 2: Preclinical Research

Once a lead compound is found, drug development begins with preclinical research
to determine the efficacy and safety of the drug. Researchers determine the
following about the drug:

Absorption, distribution, metabolization, and excretion information

of action
Potential benefits and mechanisms
Best dosage, and administration route
Side effects/adverse events
Effects on gender, race, or ethnicity groups
Interaction with other treatments
Effectiveness compared to similar drugs
 Preclinical trials test the new drug on non-human subjects for efficacy, toxicity,
and pharmacokinetic (PK) information. These trials are conducted by scientists in
vitro and in vivo with unrestricted dosages.

Absorption, Distribution, Disposition, Metabolism, &

Excretion
Absorption, Distribution, Disposition, Metabolism, & Excretion (ADME) is a PK
process of measuring the ways the new drug affects the body. ADME involves
mathematical descriptions of each effect.

Proof of Principle / Proof of Concept

Proof of Principle (PoP) are studies that are successful in preclinical trials and
early safety testing. Proof of Concept (PoC) terminology is used almost
interchangeably with PoP in drug discovery and development projects. Successful
PoP/PoC studies lead to program advancement to the Phase II studies of
dosages.
 In Vivo, In Vitro & Ex Vivo Assays

These three types of studies are conducted on the whole, living organisms or cells,
including animals and humans; or using non-living organisms or tissue extract. In
vivo, preclinical research examples are the development of new drugs using mice,
rat, and dog models. In vitro is research conducted in a laboratory. Ex vivo uses
animal cells or tissues from a non-living animal. Examples of ex vivo research
assays are finding effective cancer treatment agents; measurements of tissue
properties (physical, thermal, electrical, and optical); and realistic modeling for
new surgical procedures. In an ex vivo assay, a cell is always used as the basis for
small explant cultures that provide a dynamic, controlled, and sterile environment.

In Silico Assays
In silico assays are test systems or biological experiments performed on a computer or
via computer simulation. These are expected to become increasingly popular with the
ongoing improvements in computational power, and behavioral understanding of
molecular dynamics and cell biology.
 Drug Delivery
New drug delivery methods include oral, topical, membrane, intravenous, and inhalation. Drug
delivery systems are used for targeted delivery or controlled release of new drugs. Physiological
barriers in animal or human bodies may prevent drugs from reaching the targeted area or
releasing when they should. The goal is to prevent the drug from interacting with healthy tissues
while still being effective.

Oral: Oral delivery of medications is reliable, cost-effective, and convenient for

patients. Oral drug delivery may not monitor precise dosages to the desired area but
is ideal for prophylactic vaccinations and nutritional regimens. Delayed action,
stomach enzyme destruction, absorption inconsistencies, or patients with
gastrointestinal issues or upset can occur, and patients must be conscious during
administration.
Topical: Topical drug delivery involves ointments, creams, lotions, or transdermal
patches that deliver a drug by absorption into the body. Topical delivery is more
useful for patient skin or muscular conditions — it is preferred by patients due to non-
invasive delivery and their ability to self-administer the medicine.
 Drug Delivery
Parenteral (IM, SC or LP Membrane): Parenteral drug delivery utilizes bodily membranes,
including intramuscular (IM), intraperitoneal (IP), or subcutaneous or (SC). It is often used
for unconscious patients and avoids epithelial barriers that are difficult for drugs to cross.
Parenteral (Intravenous): Intravenous injection is one of the fastest drug delivery absorption
methods. IV injection ensures entire doses of drugs enter the bloodstream, and it is more
effective than IM, SC, or LP membrane methods.
Parenteral (Inhalation): Inhalation drug delivery gets the drug rapidly absorbed into the
mucosal lungs, nasal passages, throat, or mouth. Problems with inhalation delivery include
difficulty delivering the optimum dosage due to small mucosal surface areas and patient
discomfort. Pulmonary inhalation drug delivery uses fine drug powders or macromolecular
drug solutions. Lung fluids resemble blood, so they can absorb small particles easily and
deliver them into the bloodstream.

Formulation Optimization & Improving Bioavailability

Formulation optimization is ongoing throughout pre-clinical and clinical stages. It
ensures drugs are delivered to the proper place at the right time and in the right
concentration. Optimization may include overcoming solub
 Step 3: Clinical Development

Once preclinical research is complete, researchers move on to clinical drug

development, including clinical trials and volunteer studies to finetune the drug for
human use.

Complexity of Study Design, Associated Cost & Implementation Issues

The complexity of clinical trial design and its associated costs and
implementation issues may affect trials carried out during this phase.
Trials must be safe and efficacious and be completed under the drug
development budget, using a methodology to ensure the drug works as
well as possible for its intended purpose. This rigorous process must be
set up correctly and enroll many volunteers to be effective.
 Clinical Trials– Dose Escalation, Single Ascending & Multiple Dose Studies
Proper dosing determines medication effectiveness, and clinical trial examine
dose escalation, single ascending, and multiple dose studies to determine the
best patient dosage.
Phase I – Healthy Volunteer Study
This phase is the first time the drug is tested on humans; less than 100 volunteers
will help researchers assess the safety and pharmacokinetics, absorption,
metabolic, and elimination effects on the body, as well as any side effects for safe
dosage ranges.

Phase II and Phase III – Studies in Patient Population

Phase II assesses drug safety and efficacy in an additional 100-500 patients, who may receive a
placebo or standard drug previously used as treatment. Analysis of optimal dose strength helps create
schedules while adverse events and risks are recorded. Phase III enrolls 1,000-5,000 patients, enabling
medication labeling and instructions for proper drug use. Phase III trials require extensive collaboration,
organization, and Independent Ethics Committee (IEC) or Institutional Review Board (IRB) coordination
and regulation in anticipation of full-scale production following drug approval.
 Biological Samples Collection, Storage & Shipment
During clinical trials, biological samples are collected, stored, and shipped from
testing sites according to global standards and regulations. Transport containers
of biological samples may include dry ice packs or other temperature stabilizing
methods. Different requirements apply to different types of biological samples.

Pharmacodynamic (PD) Biomarkers

PD biomarkers are molecular indicators of the drug’s effects on the target human
area, and link drug regimen and biological responses. This data can help select
rational combinations of targeted agents and optimize drug regimens and
schedules. Rationality and hypothesis-testing power are increased through the use
of PD endpoints in human trials.
Pharmacokinetic Analysis
Pharmacokinetic analysis is an experimental trial that determines the theory of
how a new drug behaves in the human body. The volume of distribution,
clearance, and terminal half-life are defined through compartmental modeling.
 Bioanalytical Method Development and Validation
Bioanalytical methods detect analytes and metabolites such as drug or
biomarkers in biological or human samples to determine drug efficacy and
safety. The complete bioanalytical assay consists of sample collection, clean-up,
analysis, and detection.

Drug (Analyte) & Metabolite Stability in Biological Samples

Stability is important in determining human drug efficacy, and biological samples
are required. Drug and drug metabolites are susceptible to degradation, which
can lower drug concentration over the life of the drug.

Blood, Plasma, Urine & Feces Sample Analysis for Drug and Metabolites
Biological samples used in clinical trials include blood, plasma, urine, and feces to
determine and analyze various properties and effects of the drug and its
metabolites on humans.
Patient Protection – GCP, HIPAA, & Adverse Event Reporting

Human patients must always be protected during clinical trials,

and Good Clinical Practices (GCP), the Health Insurance
Portability and Accountability Act (HIPAA), and adverse event
reporting to IEC/IRB regulates and ensures their safety.
 Step 4: FDA Review
Once the new drug has been formulated for its best efficacy and safety, and the
results from clinical trials are available, it’s advanced forward for wholistic FDA
review. At this time, the FDA reviews and approves, or does not approve, the drug
application submitted by the drug development company.

Regulatory Approval Timeline

The new drug regulatory approval timeline may be standard, fast track,
breakthrough, accelerated approval, or priority review depending on its applications
and necessity for patients. If standard or priority review is required, the approval
timeline may be up to an year. Fast track, breakthrough, or accelerated approvals
may occur sooner.
 IND Application
IND applications are submitted to the FDA before starting clinical
trials. If clinical trials are ready to be conducted, and the FDA has not
responded negatively about the drug, developers may start the trials.

NDA / ANDA / BLA Applications

An NDA abbreviated new drug application (ANDA), or BLA is submitted
to the FDA after clinical trials demonstrate drug safety and efficacy. The
FDA reviews study data and decides whether to grant approval or not.
Additional research or an expert advisory panel may be required before
a final decision is made.
Orphan Drug
An orphan drug is intended to treat disease so rare that financial
sponsors are unwilling to develop it under standard marketing
conditions. These drugs may not be approved quickly or at all.

Accelerated Approval
New drugs may be granted accelerated approval if there is strong
evidence of positive impact on a surrogate endpoint instead of
evidence of impact on actual clinical benefits the drug provides.
Expedition of approval means the medication can help treat severe or
life-threatening conditions.
 Reasons for Drug Failure
New drug applications may fail for a variety of reasons, including toxicity, efficacy, PH properties,
bioavailability, or inadequate drug performance.

Toxicity: If the toxicity of a new drug is too high in human or animal patients, the
drug may be rejected due to safety concerns about its use following manufacture.
Efficacy: If a new drug’s efficacy is not high enough or evidence is inconclusive, the
FDA may reject it.
PK Properties or Bioavailability: PK properties or poor bioavailability due to low
aqueous solubility, or high first-pass metabolism, may also cause a drug to fail FDA
review. PK causes of drug failure include inadequate action duration and
unanticipated human drug interactions.
Inadequate Drug Performance: If the new drug performs the desired function, but
only at a shallow level, the FDA may reject the application in favor of a formulation
that performs better.

 STEP 5: POST MARKET

MONITORING
Following drug approval and manufacturing, the FDA requires drug
companies to monitor the safety of its drug using the FDA Adverse
Event Reporting System (FAERS) database. FAERS helps FDA
implement its post-marketing safety surveillance program. Through
this program, manufacturers, health professionals, and consumers
report problems with approved drugs.
Here’s a summary of the FDA drug approval process discussed thus far.

 Relevant Drug Development Concepts

Drug Master File

A Drug Master File (DMF) is a submission to the FDA used to provide confidential,
detailed information about facilities, processes, or articles used in the
manufacturing, processing, packaging, and storing of a human drug.

Drugs for Pediatric Use

Drugs for pediatric use are intended for use in children or youth, generally under the
age of 21. In some cases, the American Academy of Pediatrics (AMA) may make
exceptions if a pediatrician and family agree on an older age adult.
 Drugs for

Veterinary Use

Drugs for veterinary use are intended for use in animals, pets, and livestock.
However, some veterinary drugs get their start in humans and then change to
human and animal drugs.

Small Molecule vs. Biologics

Small molecules have a variety of applications or biological functions. Large

molecules (also called biologics) are proteins with a therapeutic effect. Small
molecules work by cell signaling. Large molecule drugs are complex and may
be composed of over 1,300 amino acids. They are identical versions of human
proteins.

 Process Scale-up Differences & Difficulties

Drug development involves generating progressively larger medicine batch sizes,

and changes in processes for different-sized batches may cause unexpected
difficulties. Use of the right pharmaceutical equipment can be helpful, as well as the
discovery of parameters that affect critical process parameters (CPPs).

New drug development is a highly regulated, complicated process that requires

specialists and intense research and development skill sets in the medical research
community. All regulations and safety indications must be observed carefully, and
human and animal clinical trials subjects treated professionally and with the utmost
care.

The goal of drug development is to prevent human and animal pain and suffering
whenever possible and find and provide new drugs that we can depend on to
improve our health and happiness.
 Computer aided drug design
(CADD)

is the inventive process of finding new medications based on

the knowledge of a biological target
it involves the design of molecules that are complementary in
shape and charge to the biomolecular target with which they
interact and therefore will bind it
COMPUTER-AIDED DRUG DESIGN
(CADD)

CADD represents
computational
methods and
resources that are
used to facilitate the
design and discovery
of new therapeutic
solutions
INTRODUCTION TO CADD

Drug design with the help of computers may be used

at any of the follwing stages of drug discovery:
hit identification using virtual screening (sctructure
or ligand-based design)
hit-to-lead optimization: optimization of other
pharmaceutical properties while maintaining affinity

To change from:
random screening against disease assays
Natural products, synthetic chemicals
INTRODUCTION TO CADD

To:
rational drug design and testing
speed-up screening process
efficient screening (focused, target directed)
De novo design (target directed)
Integration of testing into design process
Fail drugs fast (Remove hopeless ones as early as
possible)
Types of drug design
ligand-based drug design
relies on knowledge of other molecules that bind to the biological target of
interest.
used to derive a pharmacophore model that defines the minimum necessary
structural characteristics a molecule must possess in order to bind to the target
a model of the biological target may be built based on the knowledge of what
binds to it and this model in turn may be used to design new molecular entities
that interact with the target
Alternatively, a quantitative structure-activity relationship in which a correlation
between calculated properties of molecules and their experimentally determined
biological activity, may be derived. These QSAR raltionships in turn may be used
to predict the activity of new analogs
structure-based drug design
relies knowledge of the 3 dimensional structure of the biological target
obtained through:
1. x-ray
2. nuclear magnetic resonance spectroscopy
If an experimental structure of a target is not available, it may be
possible to create a homology model of the target based on the
experimental structure of a related protein.
Homology modeling, also known as comparative modeling of protein,
refers to constructing an atomicresolution model of the "target" and an
experimental three-dimensional structure of a related homologous
protein (the "template").
structure-based drug design

> Using the structure of the biological target, candidate drugs that are
predicted to bind with high affinity and selectivity to the target may be
designed using:
interactive graphics
Intelligence of a medicinal chemist.
various automated computational procedures may be used to
suggest new drug candidates.
structure-based drug design
1) Virtual screening: . The first method is identification of new ligands for a
given receptor by searching large databases of 3D structures of small
molecules to find those fitting the binding pocket of the receptor using fast
approximate docking programs.
2) de novo design of new ligands: In this method, ligand molecules are built up
within the constraints of the binding pocket by assembling small pieces in a
stepwise manner. These pieces can be either individual atoms or molecular
fragments. The key advantage of such a method is that novel structures can
be suggested.
3) optimization of known ligands by evaluating proposed analogs within the
binding cavity.
binding site indentification
It is the first step in structure based design.
relies on identification of concave surfaces on the protein that
can accommodate drug sized molecules that also possess
appropriate "hot spots" (hydrophobic surfaces, hydrogen
bonding sites, etc.) that drive ligand binding.

Docking & Scoring

Docking attempts to find the "best" matching between two molecules It includes finding
the Right Key for the Lock To place a ligand (small molecule) into the binding site of a
receptor in the manners appropriate for optimal interactions with a receptor.
To evaluate the ligand-receptor interactions in a way that may discriminate the
experimentally observed mode from others and estimate the binding affinity.
Components of Docking
I- pre- and/or during docking:
Representation of receptor binding site and ligand
II- during docking:
Sampling of configuration space of the ligand
receptor complex
III- during docking and scoring:
Evaluation of ligand-receptor interactions
Time
Cost
Accuracy
Advantages of CADD information about the disease
screening is reduced
Database screening
less manpower is required
Success stories of CADD

> K+ ion channel blocker

structural based discovery
> Ca2+ antagonist / T-channel blocker
chemical descriptor based discovery
> Glyceraldehyde-phosphate DH inhibitors (anti-trypanosomatid drugs)
combinatorial docking
> Thrombin inhibitor
docking, de-novo design
computational tool
for drug designing
Categories of software

Databases & Draw Tools

Molecular Modeling & Homology Modeling
Binding site prediction & Docking
Ligand design Screening - QSAR
Binding free energy estimation
ADME Toxicity
 Databases
ZincDatabase, Zinc 15Database
ChEMBL
JChemforExcel
ProteinDataBank(PDB)
BindingMOAD(MotherOfAllDatabase)
PDBbind
STITCH,SMPDB
VIDEO
thank you
 Name: RONSABLE, PRINCESS L.

Direction: Enumerate the animals commonly used in laboratory testing and write
the name of the experiments being used and state the reason.

Animals Name of Experiment Reason

Rodents
1. Mice  Toxicology experiment  Small
 Teratogenicity experiment  Easy in handling and required
 Bioassay of insulin in small dosage
 Screening of analgesic and  They have similar reproductive
anticonvulsant experiment and nervous systems to
 Screening of chemotherapeutic humans
agents experiment  Highly exploring and mobile
 Genetics and cancer research
experiment
 Drug action on CNS experiment

2. Rat  Evaluation of psychopharmacological  Small in size

agents experiment  Drug required in small
 Study of analgesics and quantity
anticonvulsants experiment  Vomiting center is absent in
 Oestrus cycle, mating behaviour and oral administration is easy
lactation experiment  Do not have gall bladder and
 Gastric acid secretion experiment tonsils
 Hepatotoxicity experiment  Continous bile flow in
 Mast cells experiment intestine
 Bioassay of various hormones
 Toxicology experiment

3. Guinea pig  Evaluation of bronchodilators  Docile animal

experiment  Highly susceptible for TB and
 Anaphylactic and immunological anaphylaxis
experiment  Highly sensitive to Penicillin
 Study of histamine and and Histamine
antihistamines
 Bioassay of digitalis
 Evaluation of local anesthetics
experiment
 Hearing experiments study
 Study on anti TB drugs
 Study on ascorbic acid metabolism

4. Hamster  Immunology and virology  Availability and ease in

experiment reproduction
 Diabetis study  Relative freedom from
 Cytological investigation spontaneous diseases
 Genetics, tissue culture, and  Anatomical and psychological
radiation experiments features with unique potential
for study
 Rapid development with short
cycles
 Presence of check pouch

5. Gebril  Stroke, epilepsy, auditory studies  Ease in handling, mild and

 parasite and bacterial infections, lipid quiet nature
metabolis, heart disease studies  They are susceptible to
bacterial, viral, and parasitic
pathogens
Non-rodents
6. Rabbit  Pyrogen testing  Docile animal
 Bioassay of anti-diabetic, curare form  It has a huge caceum and long
drugs and sex hormones appendix
 Screening of agents affecting  Enzyme atropine esterase is
capillary permeability present in rabbit liver and
 Experimentation on drugs used in plasma so it can tolerate large
glaucoma doses of belladonna
 Pharmacokinetic studies  Suitable for researches on
 Cardiac studies reproduction
 Teratogenicity studies
 Miotic and mydriatics experiment

7. Dog  Anti-arrhythmic and cardiovascular  They can be easily trained for

drugs study behavioral activity
 Vaccination study  Supportive in nature for the
 Ant-hypertensive experiment experiments
 Diabetes and anti ulcer experiments  Stomach and intestinal tract
resemble human
8. Cat  Sensory systems and neuroscience  Has distinct nictitating
study membrane, used in screening
 Behavioral and biomedical research of ganglionic drugs
experiment
 Ganglionic drugs study
 Neurological problems study

9. Monkey  Drug metabolism study  They are very much similar to

 Psycho-pharmacological studies humans
 Studying drugs acting on CNS, CVS,  They have same menstrual
GIT and fertility cycle as woman
 Infertility, virology, parasitology,  They have emotional behavior
immunology experiment as human
 Structurally and functionally
similar to man
 Suitable for undertaking
psychopharmacological
studies
10. Pig  Influenza  Similar in human physiology
 Respiratory medicament  Immunological reaction can be
 GIT disease determined
 Alimentary tract resembles
human
 Susceptible to bronchitis or
pneumonia

Miscellaneous
11. Frog  Studying embryonic development  Oxygen can pass through their
 New type antibiotic experiment highly permeable skin
 Action of drugs on CNS, heart,  Anatomically their heart
neuromuscular junction contains three chambers
which is different from the
other mammals used in the
experiment
12. Pigeon  Screening models for anti-emetic  Have excellent visual acuity,
drugs color vision, and visual
 Bioassay of prolactin memory, all of which rival or
 Screening of intravenous even surpass these abilities in
anaesthetics highly visual primates.
 Standardization of cardiac glycosides
13. Zebra fish  Vertebrate embryo development  Excellent model for studying
experiment development in vertebrates
 Transgenic model study  The embryos develop
 Produce new disease models externally to the mother and
 Gene-regulation pathways study are transparent, hence easily
viewed and manipulated
14. Chicken  Development of atrial septal defect  Widely used due to ease of
experiment availability
 biological research  Good model in toxicology and
pharmacology behavior
studies
 Their development process is
quite similar to that of humans
15. Bird  embryology and development  Chickens have been
experiment domesticated for such a long
 influenza, infectious diseases, and time, there is a lot of
viral infections studies information available on their
 Pharmaceutical and Genetic physiology
Engineering  Chickens lay eggs, which
 Study of diseases including cancer means their embryos develop
 Vaccine development for chickenpox, outside the mother’s body.
smallpox, and yellow fever and other This allows researchers to
infectious diseases. monitor the development of
the chick at every stage
including development of the
nervous system, limbs
development and cell
migration.