clinical drug design

ICIP-2016, IIUM Kuantan, Pahang, Malaysia.

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Clinical Drug Design

Prof. Dr. Basavaraj K. Nanjwade M. Pharm., PhD

Department of Pharmacy Practice,The Oxford College of Pharmacy,

Bengaluru-560068, Karnataka, India.E-mail: [email protected]

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What is Drug • Drugs are chemical or biological substances that have some kind

of physiological or biochemical effect on our bodies.• They may be single compounds or a mixture of different

compounds.• Their effects are intended to be beneficial but can cause harmful side

effects in some people.• All drugs interact with specific ‘targets’ in the body, with the aim of

modifying their activity and often resulting in a therapeutic effect.• Drug targets are usually proteins but are in some cases small regions

of DNA or RNA.• Drugs work either by stimulating or blocking the activity of their

targets.

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The Ultimate Goal

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Drug Design• Drug design is the approach of finding drugs by design,

based on their biological targets.

• Typically a drug target is a key molecule involved in a particular metabolic or signaling pathway

• Other approaches may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseases state.

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Drug Design• Enzymatic physicochemical-based (e.g., brain-targeting)

CDSs: exploit site-specific traffic properties by sequential metabolic conversions that result in considerably altered properties

• Site-specific enzyme-activated (e.g., eye-targeting) CDSs: exploit specific enzymes found primarily, exclusively, or at higher activity at the site of action

• Receptor-based transient anchor-type (e.g., lung-targeting) CDSs: provide enhanced selectivity and activity through transient, reversible binding at the receptor

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Advances in Drug Design• Computer aided based drug design• Chemistry based drug design (Property-based drug

design)• Ligand based drug design• Bioinformatics based drug design• In Silica based drug design• Structured based drug design• Pharmaceutics/Biopharmaceutics based drug design• Clinical Based Drug Design

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Pharmacokinetics• Drug design strategies used to optimise binding site

interactions of modified lead compounds were described earlier.

• A compound with good binding site interactions may not be able to overcome the obstacles interfering with the compound’s ability to reach the target.

• A compound with optimised binding site interactions may be susceptible to enzymatic degradation.

• Most drugs in clinical use are orally administered. • Methods used to improve drug absorption, distribution, site-

specificity, and metabolic stability must be used alongside strategies used to improve binding site interactions.

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Pharmacokinetics

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Drug Design for Oral Route• Log P is less than +5

• Molecular mass is less than 500 Da

• Hydrogen bond acceptors must not be greater than 10

• Hydrogen bond donors must not be greater than 5

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Design and Development

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Phase I Clinical Trial(INITIAL SAFETY TESTING IN A SMALL GROUP OF HEALTHY VOLUNTEERS )

• In Phase I trials the candidate drug is tested in people for the first time. • These studies are usually conducted with a small number of healthy

volunteers, generally 100 or less. • The main goal of a Phase I trial is to assess the safety of the medicine

when used in humans. • Researchers look at the pharmacokinetics of a drug: How is it absorbed? • How is it metabolized and eliminated from the body? • They also study the drug’s pharmacodynamics: Does it cause side

effects? • These closely monitored trials are designed to help researchers

determine what the safe dosing range is and if the candidate medicine should move on to the next stage of development.

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Phase I• Patients: 20 to 100 healthy volunteers or people with

the disease/condition.

• Length of Study: Several months

• Purpose: Safety and dosage • Percentage of Drugs that Move to the next Phase

70%

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Study Types Included• Safety & Tolerability studies (Single/ multiple dose in

patients or healthy volunteers)

• Oncology studies in patients with tolerability / MTD as primary endpoint (efficacy might be a secondary endpoint)

• Drug-Drug interaction & Food Effect

• PK in renal or hepatic impaired patients

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Phase II Clinical Trial(ASSESS SAFETY AND EFFICACY IN A SMALL GROUP OF PATIENTS)

• In Phase II trials researchers evaluate the candidate drug’s effectiveness in 100 to 500 patient volunteers with the disease or condition under study.

• Researchers also analyze optimal dose strength and schedules for using the drug and examine the possible short-term side effects (adverse events) and risks associated with the drug.

• If the drug continues to show promise, they prepare for the much larger Phase III trials.

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Phase II• Phase IIA: Exploratory (non-pivotal) study that has

clinical efficacy, Pharmacodynamics or biological activity as primary endpoint, conducted in patients or healthy volunteers.

• Phase IIB: Definite dose range finding study in patients with efficacy as primary endpoint.

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Phase II• Patients: Up to several hundred people with the

disease/condition.

• Length of Study: Several months to 2 years

• Purpose: Efficacy and side effects • Percentage of Drugs that Move to the Next Phase

33%

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Study Type Included• Proof of concept, efficacy, or mechanism

• Mechanistic studies

• Dose range exploration

• Pilot studies

• Definite dose finding studies

• Extension studies of Phase IIB studies

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Phase III Clinical Trial(DEMONSTRATE SAFETY AND EFFICACY IN A LARGE GROUP OF PATIENTS)

• Phase III trials generate statistically significant data about the safety, efficacy and the overall benefit-risk relationship of the investigational medicine.

• Phase III trials may enroll 1,000 to 5,000 patients or more across numerous clinical trials sites around the world.

• This phase of research is essential in determining whether the drug is safe and effective.

• It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g., information on potential interactions with other medicines, specific dosing instructions, etc.)

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Phase III• Patients: 100 to 5000 volunteers who have the disease

or condition

• Length of Study: 1 to 4 years

• Purpose: Efficacy and monitoring of adverse reactions

• Percentage of Drugs that Move to the Next Phase 25-30%

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Phase III• Phase IIIA: A Pivotal study that is a trial designed &

executed to get statistically significant evidence of efficacy and safety as required NDA/ sNDA approval. It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g., information on potential interactions with other medicines, specific dosing instructions, etc.)

• Phase IIIB: A study started prior to approval and whose primary intention is support of publications rather than registration or label changes. The results are not intended to be included in the submission dossier.

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Study Time Included

• Pivotal studies (vs placebo/comparator)• Long term safety studies for registration• Local registration studies• Post marketing study commitments• Phase IIIA extension studies• Studies intended to support publication, claims or

to prepare launch, which start before approval but are not intended for Regulatory submissions

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Phase IV

• Phase IV: A study started after approval with primary intention to support publications rather than registration or label changes.

• The results are not intended to be included in a submission dossier.

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Phase IV Clinical Trial

• Patients: Several thousand volunteers who have the disease/condition

• Purpose: Safety and efficacy

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Steps in Pharmaceutical Products

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Quality by Design (QbD)• QbD became the answer to assisting both the industry

and FDA to move toward a more scientific, risk-based, holistic and proactive approach to pharmaceutical development.

• In the QbD paradigm, a product is designed so that it will meet its desired clinical performance.

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Medicines research

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Clinical Design Space• The concept of clinical design space can be used to

quantify the clinical experience with a product.

• The size of the clinical design space for a given product will depend on the number of manufactured lots put in the clinic.

• The clinical design space should be given consideration, patient safety should not be jeopardized.

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REFERENCES• http://www.yourgenome.org/facts/how-are-drugs-desi

gned-and-developed.

• http://cenblog.org/the-haystack/2012/02/drug_design/• Anurag S Rathore & Helen Winkle Quality by design

for biopharmaceuticals. Nature Biotechnology 27, 26 - 34 (2009), doi:10.1038/nbt0109-26.

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http://www.yourgenome.org/facts/how-are-drugs-designed-and-developed

http://www.yourgenome.org/facts/how-are-drugs-designed-and-developed

http://cenblog.org/the-haystack/2012/02/drug_design/


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THANK YOUE-mail: nanjwadebk @gmail.com

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clinical drug design

Health & Medicine