Drug Research

Kuliah Farmasi Kuliah Farmasi Industri 2Industri 2

Drug DevelopmentDrug Development

Riset/Pengembangan Riset/Pengembangan Obat Obat

Mengapa perlu :Mengapa perlu : Belum ada obatnya : HIV / DBD/AVFBelum ada obatnya : HIV / DBD/AVF Mencari yg lebih ideal : Mencari yg lebih ideal :

ampuh/aman/terjangkau/praktis,dlsb .ampuh/aman/terjangkau/praktis,dlsb . Mis : Obat TBC , malaria Mis : Obat TBC , malaria Perluasan product rangePerluasan product range Inovasi bentuk sediaan Inovasi bentuk sediaan

Faktor2 pentingFaktor2 penting

Tingkat kebutuhan : Data demografis, Tingkat kebutuhan : Data demografis, epidemiologis, disease burdenepidemiologis, disease burden

Potensi ekonomi : volume, segmen Potensi ekonomi : volume, segmen pasar pasar

Keterjangkauan : harga vs segmen Keterjangkauan : harga vs segmen pasar pasar

Potensi pasar jangka panjang : Potensi pasar jangka panjang : perkiraan siklus hidup produkperkiraan siklus hidup produk

Tantangan Tantangan pengembangan obatpengembangan obat

Profil produk yang idealProfil produk yang ideal BiayaBiaya Uji klinisUji klinis Aspek2 regulasiAspek2 regulasi

Global Impact of Global Impact of malaria*malaria*

Endemic countries : 101Endemic countries : 101 Deaths/year : 1.2 millionDeaths/year : 1.2 million Clinical cases/year : 300 – 500 Clinical cases/year : 300 – 500

millionmillion

* * WHO report 2003WHO report 2003

The Pharmaceutical Industry and New Drug Development

US pharmaceutical industry leads the world in drug production and sales:77 billion in 1995

Invests more of its revenue in R&D than any other industry

In the R&D lifecycle, prominent role of clinical trials

R & D Lifecycle

Discovery or creation of a new compound Devise methods to synthesize compounds reliably Screen the biological activity in animal and in vitro

models Conduct tests to describe animal pharmacology,

toxicology,and pharmacokinetics Compound that show promise in preclinical testing

advances to clinical development Determine systemically safety, tolerability and efficacy in

humans

R & D Lifecycle IND (Notice of claimed exemption for a new drug) application to

FDA

IND documents consist of biology,chemistry and toxicology determined to date for new drug

Describes in detail proposed clinical studies sponsor will conduct to establish safety and efficacy for human use

For approval to market, FDA requires sponsor to conduct series of studies to document safety and therapeutic value

3 phases of Clinical Trials

Phase 1Clinical Pharmacology Initial introduction into human subjects after appropriate

preclinical safety studies Almost always inpatient studies with healthy volunteers

(cancer and rare diseases exception) Emphasis on safety not effectiveness Subject tolerance and adverse clinical effects,lab effects

observed as drug dosage is increased in amount and frequency Studies may include drug metabolism,PK,mechanism of

action Estimates dose to be used in subsequent trials

Phase II

Controlled Clinical Trials Evaluate the effectiveness of the new drug in a small

number of patients with the target disease Better define the dose and regimen Examine short term adverse events or other risk Objectively measure drug effectiveness Chiefly in outpatient patients Most trials have placebo control group(exception:oral

contraceptives,most anti infectives,cancer chemotherapy) Efficacy,dose regimen,safety profile reasonably well

defined by end of phase 11

Phase IIIExpanded clinical trials Expand phase 11 trials by enrolling large number of patients patients

to evaluate effectiveness and further safety profile Large scale multicentre trials Studies in special population: children,elderly,subjects in impaired

organ functions Model future presciption ie define drug’s effectiveness in routine and

special populations,provide fuller definition of common side effects and uncommon adverse events

Benefit to risk relationship Cost effectiveness (pharmacoeconomics) Impact on quality of life Interactions with other drugs Develop labeling for marketing presciption

The Marketing application

NDA ( New drug application) Sponsor’s request for FDA approval to market Submitted after clinical studies completed and sponsor satisfied new

drug demonstrated to safe and effective for intended use Documents: Overall summary of project Manufacturing and control data Reports from all preclinical studies Clinical summary of entire development program All protocols,CRF,related raw data Summaries of each clinical study Published and unpublished reports on drug Proposed package insert

Phase IV

Post marketing studies Performed after new drug approval Define efficacy/safety for unapproved indications Compare efficacy/safety vs marketed competitors Cost effectiveness of new drug Define new dosing regimens

Typical times to develop a new drug

Stage of development

Discovery to IND Phase I

Phase II

Phase III

NDA,FDA review & approval

TOTAL

Range(yrs) Average

0.5-2.5 1.5 0.5-1.5 1.0

1.0-5.0 2.5

1.0-5.0 3.0

1.0-5.0 2.0

4.0-19.0 10.0

Drug Development : high risk ,low yield

5,000-10,000 synthesized compounds 1000 screened 100 preclinically tested 10 clinically tested 1-2 marketed

Rancangan ProdukRancangan Produk

1. Tahap2 Formulasi 1. Tahap2 Formulasi ::

PreformulasiPreformulasi Formulasi (Skala Formulasi (Skala

lab)lab) Tahap evaluasi Tahap evaluasi

stabilitasstabilitas Scale upScale up

2. Sifat2 bahan :2. Sifat2 bahan : Bahan berkhasiat Bahan berkhasiat Bahan penolongBahan penolong WadahWadah KemasanKemasan

3. Bentuk sediaan 3. Bentuk sediaan

PRODUCT DEVELOPMENT PRODUCT DEVELOPMENT PROCESSPROCESS

LENGTHYLENGTHY -- product formulation 1-2 yearsproduct formulation 1-2 years-- Local registration ½ - 1 yearLocal registration ½ - 1 year-- WHO pre-qualification 1-2 WHO pre-qualification 1-2

yearsyearsEXPENSIVEEXPENSIVE -- Materials for experimental Materials for experimental

pilot batches.pilot batches.-- Biostudies especially for FDC’sBiostudies especially for FDC’s-- Retention of appropriate Retention of appropriate technical skills.technical skills.

PRODUCT DEVELOPMENT PRODUCT DEVELOPMENT PROCESSPROCESS

RISKYRISKY -- No guarantees for successNo guarantees for success

-- Domestic markets too small Domestic markets too small for viability while for viability while

pursuing pursuing WHO pre-WHO pre-qualification.qualification.

-- If successful can If successful can realistically realistically expect expect return in 5 years.return in 5 years.

CHALLENGES AND SOLUTIONSCHALLENGES AND SOLUTIONS

THE TRIAD/AXIS OF SUCCESS – GVNT +DRA & WHO THE TRIAD/AXIS OF SUCCESS – GVNT +DRA & WHO + COMPANY+ COMPANY

STRONG COMPLEMENTARY INDUSTRY –especially STRONG COMPLEMENTARY INDUSTRY –especially for packaging and Engineeringfor packaging and Engineering

BUILDING STRONG CHEMICAL MANUFACTURING BUILDING STRONG CHEMICAL MANUFACTURING INDUSTRY FOR ARV APIs.INDUSTRY FOR ARV APIs.

MIGRATION OF SKILLS – over 200 P’cists to UK in one MIGRATION OF SKILLS – over 200 P’cists to UK in one year (over 7 years national output of P’cists)year (over 7 years national output of P’cists)

VERY STRONG R & D – INVEST IN THISVERY STRONG R & D – INVEST IN THIS

THANK YOU

FOR YOUR ATTENTION

Drug/Chemical Action/Clinical Use Plant Source

Acetyldigoxin Cardiotonic Digitalis lanata

Adoniside Cardiotonic Adonis vernalis

Aescin Anti-inflammatory Aesculus hippocastanum

Aesculetin Anti-dysentery Frazinus rhychophylla

Agrimophol Anthelmintic Agrimonia supatoria

Ajmalicine Circulatory Disorders Rauvolfia sepentina

Allantoin Vulnerary Several plants

Allyl isothiocyanate Rubefacient Brassica nigra

Anabesine Skeletal muscle relaxant Anabasis sphylla

Andrographolide Baccillary dysentery Andrographis paniculata

Anisodamine Anticholinergic Anisodus tanguticus

Plant Based Drugs and Medicines


Anisodine Anticholinergic Anisodus tanguticus

Arecoline Anthelmintic Areca catechu

Asiaticoside Vulnerary Centella asiatica

Atropine Anticholinergic Atropa belladonna

Benzyl benzoate Scabicide Several plants

Berberine Bacillary dysentery Berberis vulgaris

Bergenin Antitussive Ardisia japonica

Betulinic acid Anticancerous Betula alba

Borneol Antipyretic, analgesic, antiinflammatory

Several plants

Bromelain Anti-inflammatory, proteolytic

Ananas comosus

Caffeine CNS stimulant Camellia sinensis



Camphor Rubefacient Cinnamomum camphora

Camptothecin Anticancerous Camptotheca acuminata

(+)-Catechin Haemostatic Potentilla fragarioides

Chymopapain Proteolytic, mucolytic Carica papaya

Cissampeline Skeletal muscle relaxant Cissampelos pareira

Cocaine Local anaesthetic Erythroxylum coca

Codeine Analgesic, antitussive Papaver somniferum

Colchiceine amide Antitumor agent Colchicum autumnale

Colchicine Antitumor agent, anti-gout

Colchicum autumnale

Convallatoxin Cardiotonic Convallaria majalis

Curcumin Choleretic Curcuma longa



Cynarin Choleretic Cynara scolymus

Danthron Laxative Cassia species

Demecolcine Antitumor agent Colchicum autumnale

Deserpidine Antihypertensive, tranquillizer

Rauvolfia canescens

Deslanoside Cardiotonic Digitalis lanata

L-Dopa Anti-parkinsonism Mucuna sp

Digitalin Cardiotonic Digitalis purpurea

Digitoxin Cardiotonic Digitalis purpurea

Digoxin Cardiotonic Digitalis purpurea

Emetine Amoebicide, emetic Cephaelis ipecacuanha

Ephedrine



Etoposide Antitumor agent Podophyllum peltatum

Galanthamine Cholinesterase inhibitor Lycoris squamigera

Gitalin Cardiotonic Digitalis purpurea

Glaucarubin Amoebicide Simarouba glauca

Glaucine Antitussive Glaucium flavum

Glasiovine Antidepressant Octea glaziovii

Glycyrrhizin Sweetener, Addison's disease

Glycyrrhiza glabra

Gossypol Male contraceptive Gossypium species

Hemsleyadin Bacillary dysentery Hemsleya amabilis

Hesperidin Capillary fragility Citrus species



Hyoscyamine Anticholinergic Hyoscyamus niger

Irinotecan Anticancer, antitumor agent

Camptotheca acuminata

Kaibic acud Ascaricide Digenea simplex

Kawain Tranquillizer Piper methysticum

Kheltin Bronchodilator Ammi visaga

Lanatosides A, B, C Cardiotonic Digitalis lanata

Lapachol Anticancer, antitumor Tabebuia sp.

a-Lobeline Smoking deterrant, respiratory stimulant

Lobelia inflata

Menthol Rubefacient Mentha species

Methyl salicylate Rubefacient Gaultheria procumbens



Monocrotaline Antitumor agent (topical)

Crotalaria sessiliflora

Morphine Analgesic Papaver somniferum

Neoandrographolide Dysentery Andrographis paniculata

Nicotine Insecticide Nicotiana tabacum

Nordihydroguaiaretic acid

Antioxidant Larrea divaricata

Noscapine Antitussive Papaver somniferum

Ouabain Cardiotonic Strophanthus gratus

Pachycarpine Oxytocic Sophora pschycarpa

Palmatine Antipyretic, detoxicant Coptis japonica

Papain Proteolytic, mucolytic Carica papaya



Phyllodulcin Sweetner Hydrangea macrophylla

Physostigmine Cholinesterase Inhibitor Physostigma venenosum

Picrotoxin Analeptic Anamirta cocculus

Pilocarpine Parasympathomimetic Pilocarpus jaborandi

Pinitol Expectorant Several plants

Podophyllotoxin Antitumor anticancer agent

Podophyllum peltatum

Protoveratrines A, B Antihypertensives Veratrum album

Pseudoephredrine* Sympathomimetic Ephedra sinica

Pseudoephedrine, nor- Sympathomimetic Ephedra sinica

Quinidine Antiarrhythmic Cinchona ledgeriana



Qulsqualic acid Anthelmintic Quisqualis indica

Rescinnamine Antihypertensive, tranquillizer

Rauvolfia serpentina

Reserpine Antihypertensive, tranquillizer

Rauvolfia serpentina

Rhomitoxin Antihypertensive, tranquillizer

Rhododendron molle

Rorifone Antitussive Rorippa indica

Rotenone Piscicide, Insecticide Lonchocarpus nicou

Rotundine Analagesic, sedative, traquillizer

Stephania sinica

Rutin Capillary fragility Citrus species



Salicin Analgesic Salix alba

Sanguinarine Dental plaque inhibitor Sanguinaria canadensis

Santonin Ascaricide Artemisia maritma

Scillarin A Cardiotonic Urginea maritima

Scopolamine Sedative Datura species

Sennosides A, B Laxative Cassia species

Silymarin Antihepatotoxic Silybum marianum

Sparteine Oxytocic Cytisus scoparius

Stevioside Sweetner Stevia rebaudiana

Strychnine CNS stimulant Strychnos nux-vomica



Taxol Antitumor agent Taxus brevifolia

Teniposide Antitumor agent Podophyllum peltatum

a-Tetrahydrocannabinol(THC)

Antiemetic, decrease occular tension

Cannabis sativa

Tetrahydropalmatine Analgesic, sedative, traquillizer

Corydalis ambigua

Tetrandrine Antihypertensive Stephania tetrandra

Theobromine Diuretic, vasodilator Theobroma cacao

Theophylline Diuretic, brochodilator Theobroma cacao and others

Thymol Antifungal (topical) Thymus vulgaris



Topotecan Antitumor, anticancer agent Camptotheca acuminata

Trichosanthin Abortifacient Trichosanthes kirilowii

Tubocurarine Skeletal muscle relaxant Chondodendron tomentosum

Valapotriates Sedative Valeriana officinalis

Vasicine Cerebral stimulant Vinca minor

Vinblastine Antitumor, Antileukemic agent

Catharanthus roseus

Vincristine Antitumor, Antileukemic agent

Catharanthus roseus

Yohimbine Aphrodisiac Pausinystalia yohimbe

Yuanhuacine Abortifacient Daphne genkwa

Yuanhuadine Abortifacient Daphne genkwa
