Exam 1 Hong

What are the steps of the Drug Development Cycle

1) Discovery, 2-4 years

2) Preclinical, 1-2 years

3) IND

4) Clinical Trials, 4-6 years

5) New drug approval

6) Post-marketing surveillance, 1-4 years

Understand the role of the Food and Drug Administration (FDA) in the drug development and review process in the US

•Regulates pharmaceutical market

•Ensuring human safety & efficacy

•Federal food, drug and cosmetic act 

Discovery

•Biology experts share knowledge of target and develop tools to further study

•Chem engages to identify chemical matter to interact with desired target

•ADME experts understand what body does to drug

•Toxicology experts for safety

•Pharmacuetical sciences- expert in formulation and delivery

Target identification then validation

→Clinical proof of concept (POC)= right target + right drug

Creation of New Drug Moecule

Canditiate selection stage→ basic material properties, in vitro cell testing, animal

Lead optimization

→Improve safety and efficiacy, SAR

Preclinical

Preclinical stage→Detailed material properties, in vitro safety testing, two animal species testing

PreClinical testing→ Therapeutic index Toxic Concen/Efficacous Concen

Drug substance scale up→ Make enough drug to use up through early clinical studies

IND Application (Investigational New Drug)

•Must be approved prior to First in Human clinical trial

•Contains: Acute toxicity in 2 species of animals, short term toxicity studies, pharmacological profile of drug substance

Phase 1 Clinical Trials

•FIH dosing to healthy volunteers

•Admin of single escalating doses of drug to small number of subjects

•Short term multiple doses

•10-15 volunteers

•Assess safety & PK

Phase 2 Clinical Trials

•First dosing to patients

•Fewer dosages studied than in Phase I

•First evaluation of efficacy

•Safety profile & PK monitored

•20-100 subjects studied

•Assess proof of concept

Phase 3 Clinical Trials

•Test effectiveness of drug for particular indication in patients

•Common effects documented

•Over 1000 subjects

•Finalize prescribing label

Phase 4 Clinical Trials

•Post marketing approval studies

•More info of effectiveness and safety

•300-30000 volunteers

New Drug Application

• Proposed labeling details for the products

• Results on safety & efficacy of the drug

• Results from clinical trials

• Details on long term studies and post marketing surveillance

• Method of manufacture of drug and quality control analysis

NDA requirements (New Drug Application)

Chemistry

Manufacturing

Controls

Labeling

Testing

Animal studies

Clinical studies

Bioavailability

ANDA requirements (Abbreviated New Drug Application)

Chemistry

Manufacturing

Controls

Labeling

Testing

Bioequivalence

Cmax

Effectiveness, Safety

AUC

Exposure, effectiveness, bioavailability

Tmax

Absorption rate, input rate

T ½

Elimination Rate

Bioavailability

•Rate and extent to which an active agent is absorbed and available at the site of action & yields a therapeutic response

•Often accepted that equilibrium exists between the concentration of drug at the site of action and concentration of drug in blood

How would a drug be 100% orally bioavailable

must be completely released from the dosage form into solution, completely stable in the GI fluids, pass through GI epithelium and undergo no first-pass metabolism in the gut wall or liver, e.g. caffeine

Describe the effect of surface area on dissolution

Increased surface area leads to more rapid rates of dissolution

Noyes Whitney Equation

Calculating dissolution rate

Cs= solubility of drug

Ct= drug concentration in bulk fluid

k= dissolution rate constant

S= surface area

Lipinski’s Rule of 5

•Molecular weight <500 g/mole

•logK <5

• <5 H bond donors

• <10 H bond acceptors (N &O)

Roles of Excipients

• Promote manufacturability

• Promote Stability

• Promote bioavailability

•Promote accurate dosing

• Promote patient acceptance and convenience

•Mostly inert

Categories of drug delivery

•Immediate release

•Delayed release of one dose then full release (ex; enteric coated)

• Prolonged release to increase intervals between dosing

•Controlled release: spatial and temporal control

Therapeutic Index

Degree of separation between toxic and therapeutic doses

Types of Systemic controlled drug delivery

• Oral route

• Intravenous route

• IM or SC

• Transdermal

• Sublingual or buccal

• Intranasal

• Pulmonary

What is the goal of Controlled local drug delivery

The goal is minimum systemic absorption and optimal drug concen reaches local site