藥物

Discovery of new drugs

Why are new drugs needed?

unmet medical need; new diseases (BSE狂牛症; AIDS,

Alzheimer’s; obesity); low efficacy (dementia癡呆, cancer); side effects (antidepressants, antipsychotics);

downstream health costs; (Alzheimer’s; spinal injury; OA; RA..) cost of therapy; (Viagra, Interleukins)

sustain (維持) industrial activity; pharmaceutical industry employs thousands and makes a massive contribution to overseas

earnings收入); patent expiry

What is a drug?

Any chemical compound - sugar ???

Anything which produces a change in the body - an axe (斧 頭) ???

Define by characteristics:

1. use or potential use in diagnosis or treatment of disease 2. selective in their actions

Substance that is used, "primarily to bring about a change in some existing process or state, be it psychological,

physiological or biochemical

Chemical agents that interact with components of a Chemical agents that interact with components of a

biological system to alter the organism

biological system to alter the organism’’s function. s function.

Examples of such components, sites of drug action, are Examples of such components, sites of drug action, are

enzymes, ion channels, neurotransmitter transport enzymes, ion channels, neurotransmitter transport

systems, nucleic acids and receptors. Many drugs act by systems, nucleic acids and receptors. Many drugs act by

mimicking or inhibiting the interactions of endogenous mimicking or inhibiting the interactions of endogenous

mediators with their receptors mediators with their receptors

藥物

藥物是一集合多樣專業以團隊方式研發創造, 並經動物實驗及人 體臨床試驗, 證明安全性與有效性, 以取得政府衛生單位核准 上市的化學或生化產品.

藥物使用在人體或動物大多不是以純粹有效成分(Active

Pharmaceutical Ingredients, “API”)方式應用, 而是以含有非有 效成分的賦型劑(Excipients)之配方劑型(Formulated Products) 方式應用.

藥物劑型及有效藥物成分

藥物劑型大致可分為

固體劑型

液體劑型

劑,液劑,或軟膏), 及

特殊藥物傳遞劑型

有效藥物成分(Active Pharmaceutical Ingredients)的來源大致來自 於化學合成,生物科技,或天然物萃取.

新藥及學名藥

藥品依專利情況又可分為新藥(New Drugs)及專利過期的學 名藥(Generic Drugs).

新藥上市需要經過嚴格的前臨床(Pre-clinical Studies)及醫 學臨床(Clinical Studies)研究證明安全與有效以取得政府 衛生單位核准, 一個新藥由新化學物質(New Chemical

Entity, NCE)的發現程序到核准上市大約平均發費15年及3 億美元, 但是一個新藥卻往往可創造年出2至10億美元的年 銷售額.

藥品製造cGMP

不論有效藥物成分或配方劑型都必須以符合藥品 cGMP(現行優良製造程序, Current Good

Manufacturing Practice)規範方式來製造, 而其製程 幾乎全為化工程序.

Drug Discovery

Biological Projects

from academia, government,

biotech and pharma Assays

Proteomics Cell & Animal Models

Cell & Animal Systems Genomics

Toxicological Testing Phase 1 Clinicals Drug Development

Bioinformatics

Target Identification & Validation Phase

High Throughput Screening, Medicinal Chemistry, Computation and Protein Phase

Licensing, Co-Development, Pharma Partner Phase Medicinal HTS

Chemistry

CompoundsLead

Validated Target

Computer Modeling

Protein Structure Protein

Production

Software ^{Cell &}

Animal Models

Diagnostics

Drug Candidates

Drug Candidates

}

Compound Library

Discovering and Developing the ‘One Drug’

Source: FDA Website ^{In lab}

Drug Candidate

safety testing

Animal Studies

- relevant species - transgenic KO/KI mice

- conditional KOs - agonists/antagonists

- antibodies - antisense

- RNAi

Studies of Disease Mechanisms

Human Studies

Phases I,II, III

Target

-receptor; -ion channel; -transporter;

-enzyme; - signalling molecule

Lead Search

-Develop assays (use of automation) -Chemical diversity

-Highly iterative process

Molecular Studies

Lead optimization

-selectivity

-efficacy in animal models -tolerability: AEs mechanism-

based or structure-based?

-pharmacokinetics -highly iterative process

Drug Approval and Registration

Target selection &

validation

Discovery Development

反覆

最佳化

Adverse events (AEs)相反

Target Selection & Validation 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.

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.

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” molecule—one that shows efficacy in an animal disease model

Optimize to give drug-like properties—pharmacokinetics, metabolism, off-target activities

Safety assessment, Preclinical Candidate!!!

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” molecule—one that shows efficacy in an animal disease model

Optimize to give drug-like properties—pharmacokinetics, metabolism, off-target activities

Safety assessment, Preclinical Candidate!!!

Discovery

Discovery

Development Development

Pharmaceutical R&D Formulation

Clinical Investigator

& patient

Clinical Pharmacology Clinical Research

Statistics & Epidemiology Data Coordination

Research Information Systems Information Services

Regulatory Affairs

Project Planning & Management Marketing

Process R&D Chem Eng. R&D

Manufacturing

Bio Process R&D Safety Assessment

Toxicology

Drug Metabolism (ADME)

Pharmacology

Pre-Clinical

Clinical

Clinical Trials Clinical

Trials

Product Profile Marketing SOI Product Profile Marketing SOI

Information Learned

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

Information Learned

1. Effectiveness in treating disease

2. Short-term side effects in health -impaired patients 3. Dose range

Information Learned

1. Benefit/risk relationship of drug

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

Compassionate Use

Phase II

Several hundred health-impaired patients Treatment Group Control Group

Phase III

Hundreds or thousands of health- impaired patients

Investigational New Drug application

IND

Phase I

20 - 100 healthy volunteers take drug for about one month

Remote data entry

Clinical Trials Continued Clinical

Trials Continued

APPROVAL PROCESS

(Ex. FDA)

Reviews, comments, and

discussions

Drug Co./Regulatory liaison activities

APPROVAL

Submit to

Regulatory Agencies

Advisory

Committee Regulatory

Review Team

New Drug Application

(NDA)

Worldwide Marketing Authorization (WMA) in other countries

Drug Discovery—Convergence of Disciplines

Patent Law Combinatorial

Chemistry

Synthetic Chemistry

Physical Chemistry

Physiology Biochemistry

DMPK

Enzymology Immunology Pharmacology Information

Technology Modelling

Physiology Safety

Assessment Metabolism

Pharmacology

Pathology

Behavior Novel

Molecule Intellectual Property

Structural Activity

Pharmacokinetic Properties In Vivo activity

Safety Design

Pharmaco- dynamics

Physiology

Physiology

Physiology

Target identification

Target validation

Lead generation

Lead optimization

Pharmacology preclinical

Manufacture Clinical trials

Regulatory Sales &

Marketing

Research/Discovery Development

Genomics Genetics (e.g. SNPs/

Haplotypes) Proteomics

Biology Functional assays Functional genomics Functional proteomics High throughput screening

ADME Assays Combi-chem High throughput screening Structure-based drug design/

Virtual screening

ADME Cheminfo/

SAR Medicinal chemistry Molecular modeling Structural biology

Animal studies In silco modeling In vitro assays

Pharmaco- genomics

Integration is both necessary &

inevitable

Drug discovery

新藥開發上市流程

上市後長期安全性監視 Phase IV Clinical Trial

申請上市送FDA審查 NDA

1000-3000名病患志願 者

有效性確認及長期使用 反應監測

Phase III Clinical Trial

100-300名病患志願者 有效性及副作用

Phase II Clinical Trial

20-80名健康志願者 安全性及劑量確認

Phase I Clinical Trial

FDA審查資料 IND

實驗室及動物試驗 安全性、生物活性試驗

Pre-Clinical Trial

實驗室、細胞株及動物 尋找新藥標的

試驗樣本及數目

試驗樣本及數目 目的

流程

Drug Actions

Therapeutic

Effects Adverse

Effects

*Side Effects *Toxicity Allergy

Less Severe More Severe

Not predictable Not dose related

*

Extension of pharmacologic effects

No drug is 100% safe

AE

Volunteer studies (phase I trials) 1. pharmacologists & employees (15-30 in number) 2. ethical (倫理道德) approval

3. healthy

4. informed consent (同意)

5. full rescussitation 可救回的+ medical backup 6. monitor

7. single and repeat doses 8. increase dose levels

OBJECTIVES

1. metabolic and excretory pathways (toxicity testing in animals)

2. variability (變異) between individuals; effect of route;

bioavailability 生物利用度 3. tolerated dose range

4. indication of therapeutic effects 5. indication of side effects

Patient studies (phase 2 trials)

1. 150-350 ill 生病 people; informed consent 2. needs license

3. maximum monitoring; full rescussitation

4. often patients where other treatment failed (一般治療差

的病人)

OBJECTIVES:

1. indication for use; type of patient; severity(隔開)of disease;

2. dose range, schedule and increment增加;

3. Pharmacokinetic studies in ill people;

4. nature of side effects and severity;

5. effects in special groups. Pharmacokinetic 藥學動力學; 化學 Pharmacodynamic 藥效學; 生物

Patient studies (phase 3 trials)

1. 1500-3500 ill patients 2. Multi center?

3. more certain data for the objectives of phase 2 studies 4. interactions between drugs start to become measurable

in the larger population

5. sub-groups start to be established

6. special features and problems show up

Clinical trials Drug action depends on:

Pharmacodynamics (藥物對生物的作用)

pharmacokinetics and dose regimen 攝取 (藥物偏化學方面的作用) drug interactions

receptor sensitivity of patient

mood/personality of patient & doctor (心情或個人因素的排除) patients expectations and past experience

social environment of patient clinical state of patient

Clinical trial controls these variables and examines action of drug in defined set of circumstances後天環境因素

Screening of compound in vitro system or silico system Successful candidate drug in rats (or mice)

Market evaluation (價值)

- jobs from entire unit can be lost in a day (工作權) - big problem for scientist retention (過去的科學家面 臨的問題)

Clinical trials Approval

- every aspect of drug is regulated

- e.g., specific manufacturing process can take years to approve .

Approaches to drug discovery

Enzymes – inhibitors (reversible, irreversible) Receptors – agonists and antagonists

Ion Channels – blockers

Transporters – uptake inhibitors

DNA – intercalating agents, minor groove binders, antisense drugs

Drug Targets and Mechanisms of Drug Action

Oral (peroral, p.o., via digestive system) Parenteral injection (through the skin)

 Subcutaneous (s.c.)

 Intramuscular (i.m.)

 Intravenous (i.v.)

 Intraperitoneal (i.p.)

Pulmonary absorption (inhalation) Intrathecal (I.T.)

Topical application (eye………)

Drug administration

半身麻醉 epidural

The changed context of drug discovery and development

The 1800s: natural sources; limited possibilities; prepared by individuals; small scale; not purified, standardized or

tested; limited administration; no controls; no idea of mechanisms.

The 1990s: synthetic source; unlimited possibilities; prepared by companies; massive scale; highly purified,

standardized and tested; world-wide administration; tight legislative control; mechanisms partly understood.

The 2000s: genomic, proteomic, mechanism, HTS……….

Discern (鑑別) unmet medical need

Discover mechanism of action of disease Identify target protein

Screen known compounds against target Chemically develop promising leads

Find 1-2 potential drugs Toxicity, pharmacology Clinical Trials

Outline of Drug Development Outline of Drug Development

Approaches to drug discovery

Historical; willow barks (aspirin); chinese medicine currently.

Study disease process; breast cancer (tamoxifen); Parkinson’s disease (L-dopa)

Study biochem/physiological pathway; renin/angiotensin

Develop to natural compound; beta-adrenoceptors (propranolol), H2-receptors (cimetidine)

Design to fit known structurally identified biological site;

angiotensin-converting enzyme inhibitors

By chance (serendipidy); random screening (HTS); penicillin;

pethidine (麻醉藥)

Genomics; identification of receptors; gene therapy; recombinant materials;

Proteomics

DRIVER IS UNMET MEDICAL NEED IN A VIABLE MARKET

胃潰瘍、十二指腸潰瘍

配西汀

藥物的來源

Animal insulin (pig, cow), growth hormone (man) Ziconotide (conus magus)…

Plant digitalis (強心劑digitalis purpurea – foxglove 毛地黄) morphine (papaver somniferum)

microbiology

Synthetic chemical (propranolol) biological (penicillin)

biotechnology (human insulin)

1. Naturally occurring Examples:

Ephedrine (麻黃素; for 安非他命), which is

extracted from plant indigenous (土產) to China, ma huang (Ephedra equisetina).

Cocaine, from the leaves of the coca plant

Opium, extracted from the unripe seed pods of the opium poppy

Discovery of new drugs

2. Semisynthetics

Examples:

Heroin (from morphine)

LSD (from fungi that grow on grain)

3. Synthetics

Examples:

Methadone (synthetic opiate)

Amphetamine (powerful stimulant)

Legal Classification (Drug Schedules)

Schedule I (heroin, psilocybin, LSD, THC, mescaline) Schedule II (morphine, cocaine, amphetamines)

Schedule III (ASA w/codeine, anabolic steroids) Schedule IV (diazepam安眠, phenothiazines)

Schedule V (cough syrup with codeine)

Unscheduled Drugs (aspirin, tylenol, Prozac)

Drug classification

抗精神病劑

止痛劑(頭痛) 百憂解

大麻所含的一種成分 迷幻藥 裸蓋菇鹼

藥 品 分 為 三 級

 成 藥

 指 示 藥

 處 方 藥

over-the-counter drugs or nonprescription drugs

Instruction drug

prescription drugs

成 藥

衛署成製字第xxxxxxxxxxxxx號

安全性比較高的藥品，普級藥品，大家都可以自由購買 但是一定要好好閱讀藥品標示與說明書

• 甲類成藥

– 金十字胃腸藥、撒隆巴斯、紅藥水 – 領有藥商許可證之商店才可販賣

• 乙類成藥

– 綠油精、曼秀雷敦軟膏

– 百貨、雜貨店或餐飲業者皆可兼營零售

over-the-counter drugs or nonprescription drugs

不用透過特別場所買的 或 非醫師處方的

指 示 藥

• 衛署藥製、藥輸字第ＸＸＸＸＸＸ號

• 安全性次高的藥品

• 輔導級藥品

• 由藥師或醫師來輔導使用

Instruction drug

治療消化道潰瘍

處 方 藥

• 限制級藥品

• 限制由醫師處方使用

• 醫師親自調劑、或由藥師調劑，交付病人使用

• 如︰威而剛、柔沛、諾美婷、RU-486

prescription drugs