Pharmacogenetics

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Questions and Answers

What is the success rate of Phase II trials in current drug development?

70% (correct)

50%

80%

90%

How much did the use of pharmacogenomics (PGx) improve the success rate of drug development from target to approval?

2-fold (correct)

5-fold

4-fold

3-fold

What is the success rate of Phase III trials in current drug development?

25-30% (correct)

60-70%

80-90%

40-50%

What is the approximate cost of current drug development per year?

$60 billion Signup and view all the answers

What is the main focus of pharmacogenomics?

Identifying genetic variants affecting drug response Signup and view all the answers

Which organization developed PharmGKB as a pharmacogenomics knowledge resource?

NIH Signup and view all the answers

How is genetic information historically used in clinics for dosage determination?

It is not routinely used Signup and view all the answers

What is pharmacogenomics highly leveraged for in personalized medicine?

Cancer treatment Signup and view all the answers

What has human genetics been historically used for in drug discovery?

Validating therapeutic targets Signup and view all the answers

What are the advantages of experiments of nature in drug discovery?

Serve as a pre-clinical model Signup and view all the answers

Which type of diabetes was used as a retrospective example in drug discovery?

Type 2 diabetes Signup and view all the answers

What is Mendelian randomization used for in epidemiological studies?

Identify target proteins/genes linked to diseases Signup and view all the answers

What is the current approach in drug discovery involving?

Using genomic/phenomic data to identify target proteins Signup and view all the answers

What does the approach in drug discovery include searching databases for?

Gain or loss of function human variants Signup and view all the answers

What do prospective examples in drug discovery include developing drugs to modify?

Specific variant proteins Signup and view all the answers

What type of data is used to identify target proteins/genes linked to diseases in drug discovery?

Genomic/phenomic data Signup and view all the answers

What is the main focus of the current approach in drug discovery?

Using genomic and phenomic data to identify target proteins and refine their regions to find genes Signup and view all the answers

What is the recent approach in drug discovery involving CRISPR focused on?

Screening for protein function in cell models Signup and view all the answers

What does classical pharmacogenetics primarily focus on?

Genes involved in pharmacokinetic and pharmacodynamic mechanisms Signup and view all the answers

What hinders the slow incorporation of pharmacogenetics into routine clinical application?

Complexity of assays, inconsistent/non-interpretable data presentation, and cost Signup and view all the answers

What do pharmacokinetic variants involve?

Drug activation, inactivation, clearance, and excretion within the body/cells Signup and view all the answers

What does PharmGKB primarily do as a knowledge resource?

Annotates genetic variants and gene-drug-disease relationships Signup and view all the answers

What is the main focus of determining molecular mechanisms of variant?

Inhibitory target proteins Signup and view all the answers

What does genomics leverage in clinical trials for the selection of participants?

Genomic data Signup and view all the answers

What is the recent discovery involving CRISPR focused on?

A protein essential for HBV protein production in a liver cell model with HBV sequence inserted in the genome Signup and view all the answers

What are pharmacodynamic variants related to?

Loss of function and gain of function variants for target proteins Signup and view all the answers

Study Notes

Pharmacogenomics in Drug Discovery and Clinical Application

Current approach in drug discovery involves using genomic and phenomic data to identify target proteins and refine their regions to find genes, followed by further characterization of the genome and phenome relationship.
Molecular mechanisms of variant are determined with a focus on inhibitory target proteins, making it easier to design inhibitory drugs, and loss of function mutations are sought to assess clinical adverse effects.
Multiple omics and big data analysis are used to infer mechanisms, followed by experimental testing using in vitro and animal models.
Genomics is leveraged in clinical trials for the selection of participants.
A more recent approach in drug discovery involves using CRISPR to screen for protein function in cell models, focusing on non-housekeeping/essential genes and developing a panel of 3,000 – 5,000 target proteins.
This approach was used in the recent discovery of a protein essential for HBV protein production in a liver cell model with HBV sequence inserted in the genome.
Classical pharmacogenetics focuses on genes involved in pharmacokinetic and pharmacodynamic mechanisms, with initial studies focusing on DNA sequence analysis to find variants and develop assays.
The slow incorporation of pharmacogenetics into routine clinical application is hindered by the complexity of assays, inconsistent/non-interpretable data presentation, and cost.
Pharmacokinetic variants involve drug activation, inactivation, clearance, and excretion within the body/cells, with main genes of interest including Cytochrome P450 enzymes, Dihydropyridine dehydrogenase, Thiopurine S-methyltransferase, and Organic acid carriers.
Pharmacodynamic variants include both loss of function and gain of function variants for target proteins, with examples such as VKOR for vitamin K activation in relation to warfarin treatment and RYR1 gene for malignant hyperthermia.
Currently, there are over 280 prescription drugs with FDA genetic testing labeling, but a low level of testing is being conducted.
PharmGKB is a knowledge resource that annotates genetic variants and gene-drug-disease relationships, summarizes important pharmacogenomic genes and associations, curates FDA drug labels containing pharmacogenomic information, and enables consortia examining important questions in pharmacogenomics.

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Description

Explore the principles and applications of pharmacogenomics in drug discovery and clinical trials, including the use of genomic and phenomic data, molecular mechanisms of variants, CRISPR screening, pharmacogenetics, and FDA genetic testing labeling.