TAHAP PENGEMBANGAN OBAT

Phase I trial Efek obat

EVALUASI OBAT Dosis, toksisitas
PHARMACOEPIDEMIOLOGY TO STUDY
BENEFICIAL DRUG EFFECTS Phase II trial Farmakokinetik

Iwan Dwiprahasto Phase III trial RCT

CE&BU, FK UGM
Phase IV trial PMS

PENDAHULUAN But, we still have a “Problem”

$800M and 12 years to develop a new drug
Obat
30 60
Pharma R&D Spending ($B)

New Drugs per Year

25 50
Efek klinik Efek Efek klinik
utama samping lain 20 40

15 30

Unanticipated harmful effects

10 20

Anticipated harmful effects

5 10

Unanticipated beneficial effects

0 0
'86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02
Anticipated beneficial effects Includes biologics. SOURCE: Datamonitor, PhRMA. Acumen Journal of Sicences, Vol 1, Issue II

Drug Development The Drug Discovery Business

Research Development
12 Years, $800M
Years: 6-8 1-2 1-2 1- 2 1- 2
Most Innovative

FDA Registration

Laboratory Research

30-40% of all new drugs fail due to poor

performance at the animal – human Least Innovative
transition
Source: National Institute for Health Care Management
The Drug Discovery Business The Drug Discovery Business

Source: National Institute for Health Care Management Source: National Institute for Health Care Management

Pendahuluan Efek obat

kloramfenikol:
Unanticipated harmful effects
anemia aplastika
BENEFICIAL EFFECTS
Anticipated harmful effects Prazosin: syncope

Aspirin:mencegah
Unanticipated beneficial effects
myocard infark
• Variasi drug regimen
• Ciri indikasi penggunaan Efficacy
• Karakteristik pasien: demografik, Anticipated beneficial effects Effectiveness
status gizi, penyakit yang Efficiency
bersamaan

Drug Discovery and

Development

Choose a disease

Choose a drug target

Identify a “bioassay”
How are drugs discovered and
developed? bioassay = A test used to determine biological activity.
 Find a “lead compound”
“lead compound” = structure that has some activity against the
chosen target, but not yet good enough to be the drug itself. • Patent the drug
• Continue to study drug metabolism
If not known, determine the structure of the “lead • Continue to test for toxicity
compound”

Choosing Choosing a
a Disease Disease

• Pharmaceutical companies
will also avoid products
• Pharmaceutical companies are that would be consumed by
commercial enterprises individuals of lower
• Pharmaceutical companies will, economic status (i.e. a
therefore, tend to avoid products with a disease which only affects
small market (i.e. a disease which only third world countries)
affects a small subset of the population)

The Orphan Drug Act

Choosing a Disease (cont.)
• Most research is
carried out on
diseases which afflict
“first world” countries:
(e.g. cancer,
cardiovascular
diseases, depression, • The Orphan Drug Act of 1983 was passed
diabetes, flu, to encourage pharmaceutical companies
migraine, obesity).
to develop drugs to treat diseases which
affect fewer than 200,000 people in the
US
 Identifying a Drug Target

• Under this law, companies who develop

such a drug are entitled to market it
without competition for seven years. • Drug Target = specific
macromolecule, or biological system,
• This is considered a significant benefit,
which the drug will interact with
since the standards for patent protection
are much more stringent. • Sometimes this can happen through
incidental observation…

Identifying a Drug Target (cont.)

• Example: In addition to their being able to inhibit the
uptake of noradrenaline, the older tricyclic
antidepressants were observed to “incidentally” inhibit
serotonin uptake. Thus, it was decided to prepare
molecules which could specifically inhibit serotonin
uptake. It wasn’t clear that this would work, but it
eventually resulted in the production of fluoxetine • Having the genetic code for the production of an
(Prozac). HO
enzyme or a receptor may enable us to over-express
N
NH2
F3C that protein and determine its structure and biological
HN
function. If it is deemed important to the disease
O
N CH3 N
H
process, inhibitors (of enzymes), or antagonists or
H3C
serotonin prozac agonists of the receptors can be prepared through a
Imipramine process called rational drug design.
(a classical tricyclic antidepressant)

Simultaneously, Chemistry is Improving! Selectivity is Important!

• This is necessary, since,
ultimately, plants and
natural sources are not
likely to provide the cures to
all diseases.
• In a process called
“combinatorial chemistry” • e.g. targeting a bacterial enzyme,
large numbers of
compounds can be prepared which is not present in mammals, or
at one time. which has significant structural
• The efficiency of synthetic differences from the corresponding
chemical transformations is enzyme in mammals
improving.
The Standards are Being Raised
Problems can
arise

• More is known about the biological
chemistry of living systems
• For example: Targeting one subtype of
receptor may enable the pharmaceutical
chemist to avoid potentially troublesome
side effects.
• Example: The chosen target, may over time,
lose its sensitivity to the drug
• Example: The penicillin-binding-protein (PBP)
known to the the primary target of penicillin in
the bacterial species Staphylococcus aureus
has evolved a mutant form that no longer
recognizes penicillin.

Choosing the Bioassay Masalah metodologi

• Definitions:
– In vitro: In an artificial environment, as in a beta blocker angina
test tube or culture media
– In vivo: In the living body, referring to tests aritmia
myocard infark
conductedin living animals
– Ex vivo: Usually refers to doing the test on a hipertensi
tissue taken from a living organism.
mencegah rekurensi

confounding myocard infark

Solusi • Can the drug have the desired effect?

• RCT ? • Does the drug actually achieve the desired effects
• Case report ? when used in practise
• Can & does the drug have other beneficial effects,
• Case series ? incl. Long-term effects for the same indication
• Longitudinal study? • Can the drug achieve these desired effects better
than other alternative drugs available for the same
indication
overdosis • What is the magnitude of the effects:
coma nalokson – variation drug regime
metadone – Characteristics of the indication
– Characteristics of patient: age, sex, race
 NSAID’s
• confounding: indikasi
• selection bias:
 severity,
Nyeri akut Osteoartritis
 tua-muda,
 penyakit sistemik,
 penyakit penyerta
 RPD,
 by chance GI bleeding

Contoh kasus 1 Masalah

• RCT : impractical
balance negatif • Post menopausal fractures: few cases
menopause kalsium & fosfor fraktur • Large sample size is needed
• Reason to receive estrogen
• Selection bias: estrogen for women who
had undergone hysterectomy (not at risk)
• Selection bias: estrogen for those at high
mencegah hilangnya risk of fractures
estrogen
bone density

Ca. endometrium

Contoh kasus 2 Masalah

menurunkan risiko recurrent
antikoagulan i.v
venous thromboembolism
berapa lama diberikan?
• RCT : impractical
• No difference in recurrence rate
• Half of the subjects: short term risk factors
for venous thromboembolism: (pregnancy,
use of oral contraceptives, recent surgery
• Less likely to benefit from longer-term
anticoagulant therapy

risiko efek lainnya?

 Contoh kasus 3 Contoh kasus 4
Vaksin
Generik vs Brand Name Drugs

Bioequivalence RCT ? Non experimental

Clinical equivalent?
Representativeness
Validity
Equivalent in efficacy and safety? Ethical
Control group

Hasil post marketing

studies
Ibuprofen R. artritis Suboptimal dose
Furosemid CHF more frequent, smaller dose
Clonidine Hipertensi tolerance jika tanpa diuretik
Metaproterenol Asthma asthma berat tidak respons
Ampisilin Otitis media bukan DOC (resistensi)