DRUG DISCOVERY

DRUG DISCOVERY

• The processes of new drug discovery and development are long, complicated and dependent upon the expertise of a wide variety of scientific, technical and managerial groups.

Why are new drugs needed?• unmet medical need; new diseases (AIDS, Alzheimer’s;

obesity); low efficacy (dementia, cancer); side effects (antidepressants, antipsychotics)

• downstream health costs; (Alzheimer’s; spinal injury)• cost of therapy; (Viagra, Interleukins)• costs to individual/country; (depression)• sustain industrial activity; pharmaceutical industry

employs thousands and makes a massive contribution to overseas earnings); patent expiry

Approaches to drug discovery• Historical; cinchona (quinine) & willow barks (aspirin);

chinese medicine currently.• Study disease process; breast cancer (tamoxifen);

Parkinson’s disease (L-dopa)• Study biochem/physiological pathway; renin/angiotensin • Develop SAR to natural compound; beta-adrenoceptors

(propranolol), H2-receptors (cimetidine)• Design to fit known structurally identified biological site;

angiotensin-converting enzyme inhibitors• By chance (serendipity); random screening (HTS);

penicillin; dimenhydramate; pethidine• Genomics; identification of receptors; gene therapy;

recombinant materials

The changed context of drug discovery and development

The 1800s: natural sources; limited possibilities; prepared by individuals; small scale; not purified, standardised or tested; limited administration; no controls; no idea of mechanisms.

The 1990s and 2000: synthetic source; unlimited possibilities; prepared by companies; massive scale; highly purified, standardised and tested; world-wide administration; tight legislative control; mechanisms partly understood, still understanding.

The New Drug Development Process

R R R

• About 2.6m animals/y used in procedures in UK (11.6m in Europe)

• Likely to increase; more research, more targets, genetic capability

• 3Rs -- 3Rs -- 3Rs• REPLACEMENT: use non-animal tests if possible

(cheaper, less trouble, less variable but not possible for everything at this time)

• REDUCTION: get the statistics right, don’t replicate work unnecessarily, don’t overbreed

• REFINEMENT: reduce suffering and severity of procedure, pay attention to housing, stress, husbandry and rich environments, proper analgesia and pre- and post- operative care

There are two types of Research: Basic and Applied

• Basic Research: discovering new facts about how things work, how they are made, or what causes a biological event to occur. Basic research can explore a topic, explain a topic or describe a topic.

• For Example: A researcher discovered that genes can be turned off or on by small RNA molecules in the body. This study was conducted on worms. It led to the Nobel Prize in 2006.

“Basic” vs. “Applied” Research

• Applied Research: Taking the information discovered in basic research and investigating how to use it to treat and prevent sicknesses.

• Example: A researcher uses the information about turning genes off and on to find a drug that is used to turn off genes that cause diseases and disorders in humans

Segment of DNA. Many such

segments act as

genes

Process of Drug Discovery

• Target Identification• Target Validation• Lead Identification• Lead Optimization• Preclinical Pharmacology and Toxicology

Target Identification• Identifying targets include

protein expression, protein biochemistry.

• Sequence analysis, positional cloning, functional cloning.

• Important to determine whether the novel targets are actually relevant to the physiology of the disease.

Target Validation• Target identified will affect an appropriate biological

response• CHEMOGENOMICS;defined as the discovery and

description of all possible drugs to all possible targets.• Chemical Genetics; involves the use of chemical probes

to understand some specific features of biology and can be viewed as subset of chemogenomics.

• LIMITATIONS;Compensatory mechanism of the organism.

Lead Identification• “lead compound”: structure that has some activity

against the chosen target, but not yet good enough to be the drug itself.

Virtual Screening

Chemoinformatics

PharmacaphoreMapping

QSAR

Docking

Chemical Genetics

• The pharmacophore is the precise section of the molecule that is responsible for biological activity.

• This may enable one to prepare a more active molecule• This may allow the elimination of “excessive”

functionality, thus reducing the toxicity and cost of production of the active material

• This can be done through synthetic modifications

Lead Optimization

• Once a lead has been discovered, it is important to understand precisely which structural features are responsible for its biological activity.

Pre-Clinical Pharmacology and Toxicology

• TOXICOLOGY• Thalidomide was developed by German pharmaceutical company

Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies

• Antiemetic = a medication that helps prevent and control nausea and vomiting

Birth defects caused by use of thalidomide

• Preclinical trial - a laboratory test of a new drug or a new medical device, usually done on animal subjects, to see if the hoped-for treatment really works and if it is safe to test on humans.

There are several steps involved with doing a Pre-Clinical Trial

• File for approval as an Investigational New Drug (IND)

• Establish Effective and Toxic Doses

Screen the Drug in the Assay

Develop a Bioassay

Indentify a Drug Target

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Scientific Aspects of Clinical Trial

Phases of Clinical Trial • Phase I (Human pharmacology and safety): First in man

safety• Phase II (Therapeutic exploration and dose ranging): First in

patient dose, dosage form• Phase III (Therapeutic confirmation/comparison) :

Efficacy, ADRs • Phase IV (Post marketing surveillance) : Evaluation in the

real clinical setting

Phase I• Objectives

1. To assess a safe & tolerated dose 2. To see if pharmacokinetics differ much from animal to man 3. To see if kinetics show proper absorption, bioavailability4. To detect effects unrelated to the expected action5. To detect any predictable toxicity

– Inclusion criteria– Healthy volunteers : Uniformity of subjects: age, sex,

nutritional status [Informed consent a must]– Exception: Patients only for toxic drugs Eg AntiHIV, Anticancer

– Exclusion criteria– Women of child bearing age, children,

• First in patient [ different from healthy volunteer]• Early phase [20 – 200 patients with relevant disease]

– Therapeutic benefits & ADRs evaluated– Establish a dose range to be used in late phase– Single blind [Only patient knows] comparison with standard drug

• Late phase [ 50 – 500]– Double blind– Compared with a placebo or standard drug

• Outcomes – Assesses efficacy against a defined therapeutic endpoint – Detailed P.kinetic & P.dynamic data – Establishes a dose & a dosage form for future trials

• Takes 6 months to 2 years [ 35% success rate

Phase II

Phase III• Large scale, Randomised, Controlled trials• Target population: 250 – 1000 patients• Performed by Clinicians in the hospital • Minimises errors of phases I and II• Methods

– Multicentric Ensures geographic & ethnic variations – Diff patient subgroups Eg pediatric, geriatric, renal impaired– Randomised allocation of test drug /placebo / standard drug– Double blinded:– Cross over design– Vigilant recording of all adverse drug reactions – Rigorous statistical evaluation of all clinical data

• Takes a long time: up to 5 years [25% success

Phase IV or Post marketing Surveillance

• No fixed duration / patient population• Starts immediately after marketing• Report all ADRs• Helps to detect

– rare ADRs– Drug interactions– Also new uses for drugs [Sometimes called Phase V]

Clinical Trial: Legal & Procedural aspects

Elements of a Clinical Trial • Aim or objective• Protocol : study design• Ethics committee clearance• Regulatory approval whenever required• Informed consent• Implementation of protocol• Collection of data• Compilation of data, analysis and interpretation• Report writing

Participating Parties in Clinical Trial1. Patient / Healthy volunteer: Subject of the trial2. Clinical Pharmacologist, Clinical Investigator & team: [Qualified and

competent] Conducts the clinical trial; reports all adverse events 3. Institution where trials are held : [Approval required] Provides all

facilities 4. Ethical Review Board or Institutional Ethical Committee: -Supervises and monitors every step;

– Safeguard the welfare and the rights of the participants – 5. Sponsor – Pays for all expenses; – Appoints competent investigators, – Ships all drugs for the trial, – Files all papers to legal / regulatory authorities,

6. Regulatory Authorities:Legal authority on the outcomes of the trial

THANKS