Transcript Advanced Data-Visualization for Drug Discovery
Using Spotfire DecisionSite to Realize the Full Value of High-Throughput Screening ADME Data
Eric Milgram
Pfizer Global Research & Development – La Jolla Spotfire Users’ Group Meeting Wednesday October 15, 2003 San Francisco, California
Challenge faced by Pharmaceutical Industry
$25
Cost and Number of NDAs per year
$20
Reduce Attrition $15
Increase Productivity $10
No growth $5
Budgetary Pressure $0 1970197119721973197419751976197719781979198019811982198319841985198619871988198919901991199219931994199519961997199819992000
Source: PhRMA annual survey, 2000
Why Do Candidates Fail?
Commercial Reasons Miscellaneous 198 NCEs Adverse effects in man 10% 5% 5% Animal Toxicity 11% 39% Pharmacokinetics 30%
Drug Discovery Today 2:436, 1997
Lack of Efficacy
The Fate of a Medication after Administration ADME
• • • • Absorption • The movement of drugs into the bloodstream or lymphatic system from the site of administration Distribution • The distribution of absorbed drugs from the absorption site to all areas of the body Metabolism • The biotransformation of drugs to more polar forms (hydrolysis, oxidation, conjugation, etc.) Excretion • The elimination of “unwanted” substances
Drug Metabolism in Drug Discovery
• Early assessment is critical, since the duration of action is dependent on structural modifications induced by
in vivo
metabolizing systems.
• Early knowledge of metabolic products permits metabolism guided structure modification schemes, such as modification of metabolic “soft spots” to achieve prolonged drug action.
• Identify pharmacologically or toxicologically active metabolites.
Physicochemical & Biochemical In- Vitro Assays
Predictive of
In-Vivo
Absorption, Distribution, Metabolism, Excretion • Solution Properties • • Solubility Log D • Protein Binding • pKa • Absorption • • PAMPA Caco-2, MDCK • P gp transport • IAM • Metabolism • Metabolic stability •
Liver microsomes hepatocytes , S-9,
• • Metabolic profile CYP450 enzyme inhibition • Safety Assessment • Cell viability • Mutagenesis (Ames) • • Glutathione level Dofetilide binding
Pritchard, et al., “Making Better Drugs: Decision Gates in Non-Clinical Drug Development” Nature Reviews: Drug Discovery, 2003 , vol 2(7), pp. 542-553. (http://www.nature.com/reviews/)
Advances in Laboratory Robotics and Instrumentation Have Been Swift
Difficulties Resulting from HTS
The rate at which we can collect data far exceeds our capacity to transform this data into information that can be used most effectively to drive important business decisions Relevance of data?
Number of data dimensions?
What do we do when two different dimensions are in conflict?
Unmasking subtleties (ie “data-mining”)
Visualization is a Powerful Tool For Data Analysis
Spotfire can be used to find trends related to how samples are formatted on plates.
PLATE_NUMBER - 1 H G F E D C B A H G F E D C B A H G F E D C B A H G F E D C B A PLATE_NUMBER - 6 PLATE_NUMBER - 11 PLATE_NUMBER - 16 2 4 6 8 10 12 PLATE_NUMBER - 2 PLATE_NUMBER - 7 PLATE_NUMBER - 12 PLATE_NUMBER - 23 Scatter Plot PLATE_NUMBER - 3 PLATE_NUMBER - 8 PLATE_NUMBER - 13 PLATE_NUMBER - 24 PLATE_NUMBER - 4 PLATE_NUMBER - 9 PLATE_NUMBER - 14 PLATE_NUMBER - 5 PLATE_NUMBER - 10 PLATE_NUMBER - 15 2 4 6 8 10 12 2 4 6 8 WELL_COLUMN 10 12 2 4 6 8 10 12 2 4 6 8 10 12
Figure 3.
Spotfire plot of variation in the internal standard for a series
How do we use Spotfire DecisionSite to Allocate Resources Efficiently?
Quality Control and Quality Assurance Results Analysis and Trending
When combined with chemometrics techniques, such as principal components analysis (PCA), Spotfire enables viewing of interesting trends in large, multidimensional data sets.
PCA (2 components) For LJ-EDT Data (human/rat liver/microsomes and caco-2 AB/BA) UNSTABLE RHEP 40 20 STABLE RLM 0 -20 -40 -60 -80 UNSTABLE RLM -125 -100 -75 -50 PCA 1 -25 0 25 50 UNSTABLE HLM 75
Spotfire enables viewing of trends that would be difficult to spot otherwise
IS Vals vs Ret Time ASSAY_TYPE ASSAY_TYPE 140000 120000 100000 80000 60000 40000 20000 0 0.2
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1 1.2
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1.6
RET_TIME_MIN 0.2
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Summary
Spotfire DecisionSite enables powerful interrogation of large data sets Ability to generate quickly new views of the same dataset is essential in a high-throughput discovery environment Sometimes, weaknesses in experiment design are uncovered Having a collection of “standard” visualizations greatly facilitates QA Integration of chemometrics tools (e.g. clustering, PCA, etc) enables researchers to “gain a deeper understanding of their data” (Data Information)