Drug Development Wegovy Assignment

biotechnology

biological technique applied to product development and research

biomedicine

use of biotechnology in clinical medicine

small molecule/pharmaceutical

small, more than one function (off target effects), organic compound, stable, oral

generic

same small molecule from a different manufacturer, cheaper

biopharmaceuticals/biologic

pharmaceutics made from biologics not a chemical entity, large complex, one specific function

biosimilar

slightly different biologic from different manufacturer, cheaper

efficacy

effectiveness under controlled conditions

effectivness

how well it works in the real world

first in class drugs

unique mechanism for treating medical condition, 36% of approvals

for orphan/rare diseases

accelerated approval (7-10 yrs), 51% of approvals

drug discovery pathway

clinical observation → idea → target identification → molecular synthesis → in vitro testing (cells) → in vivo (animals) → manufacturing and controls → safety testing → clinical testing

biomarker

way to measure how the drug works when you give it to a person

Pharmaco kinetics (PK)

how the body impacts the drug

pharmaco dynamics (PD)

what the drug is doing to the body

therapeutic index

range of drug conc that where it will have an effect but no toxicity, (toxicity/efficacy), larger range is better so its harder to get a toxic dose

drug development

drug already found but now finding best mode to take it

ADME

absorption, distribution, metabolism, excretion

Absorption

bioavailability, amount of the drug that reaches circulation system, IV has highest

Distribution

how drug is distributed through body, has to go through gi tract if oral and lungs in inhaled

Metabolism

first pass metabolism - pre systemic elimination of drug by microbiome (small molecules often gone)

Excretion

drug clearance by kidney

Biotransformation

drug becomes modified by metabolism to become its active form

Drug half-life

time it takes for the concentration of the drug in the blood to become half it’s steady state

SAR

structure activity relationship, relationship between biological activity of drug and chemical groups/structure

Lipinski Rule of 5

compound is easily absorbed by body if it is: not more than 5 hydrogen bonds donors, no more than 10 hydrogen bond acceptors, molecular weight is less than 500 Da, ClogP is not greater than 5

Nonclinical safety studies

used to establish organs it could be toxic for, safe starting dose, safety parameters for clinical trials

ICH M3

standard nonclinical requirements for a phase 1 trial

Animal testing

can look at effects of each organ, look at reproductive and developmental toxicity, lifespan, mechanism of drug

NOAEL

No observed adverse affect level, highest level of drug with no adverse effects, can be calculated form animal testing results

MABEL

Minimal anticipated biological effect level, used to find the first human testing dose

Regulations before clinical trials

International council for Harmonization, Good Manufacturing Practice, Good Clinical Practice, Declaration of Helsinki

Declaration of Helsinki

ethical principles for human experimentation, respect for individual, right to self determination, right to make informed decisions

Phase 1

safety, looking at adverse events, toxicity, side effects, small group, 75% success rate, $1-7M

Phase 2

safety and efficacy, looking at response rate, adverse events, pk, efficacy, 50-100 ppl, longer than phase 1, 35% success rate, $7-20M

Phase 2a

focuses on determining right dose

Phase 2b

focuses on determining efficacy, proof of concept

biomarker

diagnostic - used to diagnose disease, predictive - used to predict pos or neg effect from medical product, response - pk indicates change in bio process

Phase 3

efficacy, looks to confirm and convince to approve therapy, large group of ppl, 1-3 yrs, 70% success rate, $11-60M

Phase 4

effectiveness, optional after marketing approval, real world patients to detect less common adverse events, gives credibility to doctors, large impact on sales, very expensive

Fixed trials

preclinical research sets basis for parameters and can’t differ from this, greater productivity, quicker planning

Adaptive trial

longer planning stage, can end trial early and look at data throughout

Natural peptides

produced naturally and synthetically, insulin, hormones, growth factors

peptide

chain of amino acids, injection, too larger to be absorbed by intestines, very specific, expensive, less shelf stable, low toxicity, low bioavailability

Peptides from animals

risks of zoonosis and purity, formation of antibodies

Peptides from humans

risks of disease transmition, availability

Recombinant DNA technology

put gene of interest into plasmid and them back into host organism, very specific, improved affinity, biologically active by modifying sequence, resistance to degradation by change to right formation, cost and time effective

Short half-life

works in minutes, prevents over correction, preserves desensitivity with no constant exposure, keeps signaling local

Long half-life

sustained signaling, steady levels, lowers synthesis energy needed

Post translational modifications

amino acid modifications (irreversible), add of chemical groups/complex molecules/polypeptides, cleavage

Polyethylene glycol polymers (PEG)

non toxic, non immunogenic, very flexible, FDA approved, masks protein surface decreasing immunogenicity, increases size, lowers degradation