Penemuan dan

Pengembangan Obat
Drug discovery

Prof.Dr.dr. M T Kamaluddin,M.Sc.,SpFK

Bagian Farmakologi
Fakultas Kedokteran Unsri
2017
Man and Nature were interdependent

1. Only nature heals

2. Let food be your medicine
3. Disease is an expression of purification
4. All disease is one
5. It is more important what sort of
person has a disease than what sort of
disease a person has
Asclepios (3000 BC)
Father of Ancient Medicine
Rudolf Fritz Weiss (1895-1992)
Father of Folk Medicine
 WORLD HEALTH ORGANIZATION
Executive Board 117th Session
January 2006

6. In cases where medicines are needed where significant numbers of patients have
higher incomes, there is disproportionate emphasis on products that do not provide
incremental benefits over existing ones. A breakdown of the 1,035 new drugs
approved by the US FDA (Federal Drug Administration) between 1989 and 2000
revealed that more than are classed as having no therapeutic benefit over existing
products, so called me too drugs (NIHCM 2002). At the same time it was noted that
less than 1% addressed diseases that primarily afflict the poor and for which new
treatments would have the greatest effect on world healthcare (WHO 2003)
 100
120
140
160
180
200

20
40
60
80
Source: Kaiser Permanente, the largest HMO in America

400.000 Medical Mistakes

Source: Annals of Internal Medicine

198.000 Prescription Drugs Side Effects

Source: Journal of the AMA

90.000 Nosocomials

Source: Centers for Disease Control

180.000 Lung cancer

Source: Centers for Disease Control

150.000 Stroke
WHO ARE WE?

Source: Centers for Disease Control

16.000 AIDS/HIV
(average per year in 000)

8.400 Accidents (car & airlines)

Those are considered highly preventable
UNNECESSARY DEATHS

Naturopathy care = ZERO Deaths

 If all the medicine/drugs in the world were
thrown into the ocean, it would be good for
mankind and bad for the fish.

- O.W. Holmes, MD, Professor of Medicine, Harvard University

 MEDICINE TODAY

ONVENTIONAL
DISEASE
SAKIT NON CONVENTION
Pathogenese
Naturopathic Medicine
Anti Aging Medicine
DIS-EASE Wellness Medicine
SEHAT Regenerative Medicine
Physiogenese Functional Medicine
Restorative Medicine
PHYSIOGENESIS TARGET
 Conventional
Disease only treat the
PATHOGENESE
symptoms
Symptoms
Imbalances
biological Symptoms are
function caused by
imbalances in
Dis-ease the body
PHYSIOGENESE

To find the
The Person cause you
have to look
at the person
holisticly
HEALTH & MEDICAL CARE GRADING

TREATMENT

RECOVERY

REJUVENATION

REVITALIZATION
Target selection & Discovery Development
validation

Target Drug Candidate

Studies of -receptor; -ion channel; -transporter; safety testing
-enzyme; - signalling molecule
Disease Mechanisms

The Drug Discovery Process

Lead Search
-Develop assays (use of automation) Human Studies
-Chemical diversity Phases I,II, III
Molecular Studies -Highly iterative process

Animal Studies
- relevant species Drug Approval
- transgenic KO/KI mice Lead optimization and Registration
-selectivity
- conditional KOs
-efficacy in animal models
- agonists/antagonists
-tolerability: AEs mechanism-
- antibodies based or structure-based?
- antisense -pharmacokinetics
- RNAi -highly iterative process
 Target Selection & Validation

Define the unmet medical need (disease)

Understand the molecular mechanism of the disease
Identify a therapeutic target in that pathway (e.g
gene, key enzyme, receptor, ion-channel, nuclear
receptor)
Demonstrate that target is relevant to disease
mechanism using genetics, animal models, lead
compounds, antibodies, RNAi, etc.
 Discovery
Develop an assay to evaluate activity of compounds on the target
- in vitro (e.g. enzyme assay)
- in vivo (animal model or pharmacodynamic assay)
Identify a lead compound
screen collection of compounds (compound library)
compound from published literature
screen Natural Products
structure-based design (rational drug design)
Optimize to give a proof-of-concept moleculeone that shows efficacy in an
animal disease model
Optimize to give drug-like propertiespharmacokinetics, metabolism, off-
target activities
Safety assessment, Preclinical Candidate!!!
 Development
Pre-Clinical
Process R&D
Pharmacology Chem Eng. R&D
Safety Assessment Manufacturing
Toxicology
Drug Metabolism
(ADME)

Pharmaceutical R&D
Formulation Bio Process R&D

Clinical Investigator
& patient
Regulatory Affairs
Clinical Pharmacology Project Planning & Management
Clinical Research Marketing

Statistics & Epidemiology

Data Coordination
Research Information Systems
Information Services
Clinical
 Phase I Product Profile Marketing SOI
Investigational
20 - 100 healthy volunteers take
New Drug drug for about one month
application Information Learned

IND 1. Absorption and metabolism

2. Effects on organs and tissue
3. Side effects as dosage is increased

Remote data entry

Clinical Phase II
Trials Several hundred health-impaired patients Information Learned
1. Effectiveness in treating disease
Treatment Group Control Group
2. Short-term side effects in health -impaired patients
3. Dose range

Phase III Information Learned

Hundreds or thousands of health- 1. Benefit/risk relationship of drug

2. Less common and longer term side effects
impaired patients
3. Labeling information

Compassionate Use
 Clinical Advisory
Committee Regulatory
Trials Review Team
Continued
APPROVAL
Reviews,
PROCESS comments, and
(Ex. FDA)
discussions
Submit to
Regulatory Agencies
Drug Co./Regulatory
liaison activities
New Drug
Application
(NDA)
APPROVAL

Worldwide Marketing Authorization (WMA) in other countries

 Drug DiscoveryConvergence of Disciplines
Synthetic
Combinatorial Patent
Chemistry
Chemistry Law
Modelling
Novel
Intellectual
Molecule Property Physiology
Information Design Structural Biochemist
Technology
Activity ry

Physiology
Safety
Pharmacodynami Physiology
Metabolism cs
Pharmacology
Safety Properties
Assessment Immunolo
In Vivo activity Pharmacokinetic gy
Properties DMP
K
Pharmacology Behavior
Pathology
Physiolog Physical Physiology Enzymology
Chemistry
y
 Conventional Medicine
HEALTHY SICK
The aspects: You are either healthy or sick. If you are healthy you do not require
medication. If you are sick you generally will be given a prescription to control
whatever symptoms you might have

Functional Medicine
HEALTHY Vital force SICK
The goal is to restore important function within your body. If you treat the cause
of the problem, you can prevent it from developing into the full blown disease.
Treating is important but prevent relapsing is more more important
 Patient centered-care
A dynamic balance
Homeostasis vs Homeodynamics
HOMEOSTASIS HOMEODYNAMICS

State of equilibrium with respect to Range of continuously occurring

various functions and to the chemical
compositions
Milieu interieur
Fight vs Flight hypothesis
Defines how and how long our bodies
function
POSITIVE VITALITY
(not just absence of disease)
metabolic and physiologic activity that
enable an individual to adapt to changing
circumstances
Vis Medicatrix Naturae
Biochemical individuality
Require attention on cellular processes or
organ function
VITAL FORCE
EXAMPLE:
 Receptors
Signal transduction
Electron transport

Y Y Y
DNA
Transporter - Replication
- Transcription
- DNA repair

Protein
Ion Mitochondrion
biosynthesis
channels

n
u
c
l RNA
e
u
Enzymes s

lysosome

Cell membrane

Posttranslational
Cytoskeleton protein modification
(actin, microtubules)
Van Wyk (2004)
DIS-