Natural Product Sources Flashcards

Question

What happens after the patent has expired?

Answer 1

The patented drug comes out of patent protection and it typically leads to the production of the rug as generics- produced by some other company e.g. Zovirax (aciclovir), Zantac (ranitidine), Prozac (fluoxetine) The loss of market can be very dramatic

Answer 2

Once the patent has expired, generic drugs quickly overtake the sales of branded drugs. Sales data suggest it takes only 6 months before generic drugs pick up 80% of the share of sales.

Answer 3

Re formulate Rebrand New indications

Answer 4

Allows a company to develop better products, build a franchise, limit the impact of generics e.g. Prozac Weekly was approved by the FDA Two years after the original patent ended, for the same continual treatment phase of major depressive disorder. PW contains 90mg of fluoxetine with an enteric coating which delays the release into the bloodstream. This formulation takes advantage of the protective effects provided by fluoxetines naturally long half life, requiring PW only to be administered once a week. The new formulation was patented as an improved method of delivery which is safer and improved patient compliance. This stops other companies selling selling PW until 2017

Answer 5

Where pharmaceutical companies give a new brand name to a molecule and introduces it into a new market. E.g. July 2000: the FDA approved Eli Lilly's sarafem for the treatment of premenstural dysphoric disorder. It contains the same active ingredient found in Prozac. The additional patent protection also helps with educational efforts for the largely under recognised disorder. Is also reduces confusion about the differences between depression and PMDD Sarafem became the first prescription medicine indicted for the treatment of PMDD in the US

Answer 6

Where companies sell the product too treat a wider range of diseases, so the overall volume is not as heavily affected. E.g. New indications for antidepressants like Prozac include treating for OCD, panic disorders and other anxiety/stress conditions. These new indications are often heavily pushed by sales reps of the pharmaceutical companies, ensuring doctors remember their products and reminding doctors of all the conditions that their drugs can be used to treat.

Answer 7

Companies will want to patent its new drug as late in the development as possible to allow more time for it to live when the drug is on the market so that the company can gain its return of the development costs. However, they risk another company patenting the drug.

Answer 8

The applicants have one year to file a full patent. These are useful as the date of the filing (priority date) will help define who patented first, but the year of the provisional patent does not count against the term of the issued patent.

Answer 9

The companies chemical process development group undertakes the synthesis of bulk quantities of the raw drug substance . The drug is then formulated providing suitable dosage forms for clinical purposes Toxicity studies are also initiated in several animal species, investigating the metabolic disposition and pharmacokinetic properties of the drug.

Answer 10

Further development of the drug may stop.

Answer 11

Company will file an investigational new drug application with the US FDA. This is a formal request to begin the clinical trials of the drug

Answer 12

To finally evaluate the ability of the compound to provide benefit to humans

Answer 13

Four phases: 1) clinical pharmacology and toxicity 2) initial clinical investigation for treatment effect 3) full scale evaluation of treatment 4) post marketing surveillance

Answer 14

This is the first phase of clinical trials. The studies conducted in this phase are concerned with the safety of the compound. Studies are performed on ~20-100 health volunteers

Answer 15

1) single dose (often low dose) on health males 2) rising dose studies to determine an acceptable single dose via route of interest, on health males/females. This helps to establish the therapeutic range 3) food interaction studies in both health male/females

Answer 16

Drug metabolism and bioavailability studies

Answer 17

When drugs that will most likely have toxic effects e.g. New anticancer drugs. Any serious adverse effect will usually result in trials being aborted

Answer 18

15%. | The cost of trials to this point is ~$5.4M NZD

Answer 19

Safety of the new compound and beings to monitor efficacy in the selected patient population. Typically divided into 2 stages

Answer 20

1) proof of concept trial- where a limited trial is conducted in selected patients to ascertain the drug has some degree of efficacy 2) more broad range trial - which involves a larger number of patients often trial lying two different dose strengths. Required to refine the optimal dosage and determine the best way to administer the drug

Answer 21

Typically on a double blind bias. | Many Regulatory agencies also require a positive control group where patients are given a known drug

Answer 22

to validate both the trial and to demonstrate the new drug has comparable or superior efficacy and an equivalent or superior safety profile

Answer 23

In the case of life threatening diseases such as cancer, | The new drug is compared to a known medication

Answer 24

2 years, often involving 200-500 patients

Answer 25

nearly 50%. | Phase II requires $80M NZD

Answer 26

This consists of two global trials at 2 dose strengths with ~2000 people per trial The dosages used are important as these are the doses to be used if the drug is marketed, Testing is always conducted as double blind vs. Placebo/currently use drug Different racial groups will often be included to investigate a possible difference between ethnicities

Answer 27

Usually 2 years, but can take as long as 8 years if a patient numbers are low. The trial will run as long as needed to obtain sufficient info for the application to be made to the US FDA for a new drug application The FDA then takes 18 months to decide

Answer 28

More than 90%. This has costed $1.1Billion NZD

Answer 29

Post marketing surveillance Occurs after drug approval Involves monitoring of adverse effects and additional long term, large scale studies of drug efficacy. These studies can also help identify additional new uses for the drug

Answer 30

Merck has recently reduced its top selling arthritis and acute pain medication, Vioxx. A study conducted in huge use if Vioxx in treating colorectal polyps discovered patients had an increased probability of CVD events beginning after 18 months of treatment compared to those taking placebo. Merck has another drug, Arcoxia which treats arthritis and pain they are hoping to transfer patients onto without any overall loss of income. Vioxx has already easily made back the money spent on its research and development, so they can afford to let it go, still having made an overall profit

Answer 31

``` Experimental structure determination, 3D protein structures as templates for model building, Comparative modelling, Sequence of novel therapeutic targets Virtual libraries 3D models of therapeutic targets High throughput docking (in silico screening of compounds on 3D targets) Structure based library design Hits, Structure based analogue design Less ```

Answer 32

The process of using computational methods to design molecules which fit into the binding pockets on the protein This involves high level docking calculations that require powerful computers.

Answer 33

Chemists then synthesise the molecules and perform bioassays, The programmes will usually design molecules than bind extremely efficiently

Answer 34

The computer doesn't always design molecules that are easy to make. It also takes a lot of time to generate these structures for assay. They may be too complicated

Answer 35

Relenza (anti influenza medication) Inhibits salidase on the virus which mediates the hydrolysis of a polysaccharide. This is an important step in the release of new virus particles from an infected cell. To design new inhibitors of the enzyme, they crystallised the enzyme with a compound related to the normal sialic acid substrate. Resultant X-ray crystallography 3d structure allowed visualisation of the active site of enzyme. By modelling this active site, they could design molecules that would fit into it very tightly due to close interactions of opposite charged functional groups and close alignment of hydrophobic groups. After modelling, target compounds were prepared and screened against the enzyme, leading to the discovery of Relenza.

Answer 36

Lowers the substrate turn over capacity of the enzyme, | The result of enzyme inhibition is the inability of the virus to replicate and move about the body

Answer 37

They found their drug had no oral bioavailability and was only active when taken directly into lungs using an inhaler device. This limited their sales and opened up the market to its competitors. Tamiflu (sold by Roche) was then developed using "me-too" philosophy as an oral alternative to Relenza.

Answer 38

Tamiflu took the design of Relenza and adapted it to fit lipski's rulers with the sole aim of making a good oral drug. Tamiflu currently outsells Relenza on a 100:1 ratio

Answer 39

Losec = omeprazole, sold as a racemic mixture. Only one isomer is active. The other isomer is inactive and completely safe Nexium = esomperazole. Name is derived from s isomer of the racemic drug. 40mg of Losec has the same effect as 20mg of Nexium and to date, no clinical trial has shown any valid reason for taking Nexium over Losec. AstraZeneca's composition of matter patent had elapsed on Losec so by converting patients to Nexium, the company still has the financial advantage over their competition.