PharmaPendium: Metabolizing Enzymes and Transporters Module

Your presenter: Philip Maclaughlin

Welcome to our webinar!

Your host: Chris Flemming

About Us

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Agenda

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• Short Introduction to PharmaPendium

• Metabolizing Enzymes & Transporters Module

• Live Demo MET Module

• Questions and requests

What is PharmaPendium?

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First product to offer both searchable FDA approval packages and EMA EPARs• 1.7M newly-searchable pages covering all of FDA history, over 70 years

(from 1938),• Searchable EMA EPAR content (from 1995)

Used primarily for Preclinical assessment (Safety, PK, Efficacy) and Regulatory Affairs

AERS (post-marketing events)

What is PharmaPendium?

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First product to bring together preclinical, clinical & post marketing data•Normalized terminology on searches, extracted data•Which experimental data translates, why or why not?

Over 1,200,000 extracted drug safety observations•Normalized AE/Tox terminology mapped to Class, Target, Structural Chemistry

Over 1,300,000 extracted PK parameter data, preclinical and clinical. Normalized and related the same way (structure, class, target)

Metabolizing Enzymes &Transporters (MET) Module for PharmaPendium

Adverse drug interactions resulting from effects of drug metabolizing enzymes and transporters.

• These drug-metabolizing enzymes (CYPs and Phase 2) and transporters, are key players in drug/drug interactions

• Unintended/unanticipated toxicities and efficacy failures.

With our unique content assets (FDA, EMA, FDAAC), we have built adatabase with unsurpassed depth.

• Containing CYPs, Phase2 enzymes, dynamic parameters (Cint, Vmax) and transporters –

• Measured with drug as substrate, inducer or inhibitor.

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Metabolizing Enzymes &Transporters (MET) Module for PharmaPendium

Extracted Content from FDA, EMA, FDAAC, journals:

All with drug as: substrate, inducer or inhibitor

Metabolites CYPs

Transporters In Vitro DDI Studies

Created, when available Either involved in the metabolism or up/down regulated by the drug,quantitative and qualitative data

Phase 2 Enzymes

And drug effects on transporters

Dynamic parameters such as CLint (Intrinsic Clearance) and Km (Michaelis Constant), Vmax (Maximum rate of reaction)

Ratio of AUC, Clearance, etc. in presence of another drug.

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End User Problems Addressed:

What could be the result an increase in these enzymes on

other drugs?

Which CYPs’ production is likely stimulated when my

drug is administered?

How can I improve my DDI models to reflect various subject types,

doses, etc?

Which CYPs’ production is likely inhibited when my

drug is administered?

What could be the result of a decrease in these enzymes on other drugs, or the health of the

patient?

Which CYPs’ are likely to act on

my drug and metabolize it?

At what rate? What food may increase/decrease this CYP?

What effect can these enzymes and transporters have on the bioavailability of my drug within the proposed therapeutic window?

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Metabolizing Enzymes &Transporters (MET) Module for PharmaPendium

Metabolizing Enzymes &Transporters (MET) Module for PharmaPendium

Value:

Unmatched level of curation from a unique data source:

More data per drug

More experimental detail

Highest quality data

Understanding potential drug-drug interactions is critical to today’s drug approval process.

Drugs get hung up in the approval process (patent time)

Drugs fail late due to unexpected DDI’s

Drugs are withdrawn due to DDI’s (catastrophic)

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Preclinical/Clinical representation of dataExample: Anticonvulsants

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Filters applied; CYP2C8 & as “an inhibitor”

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Drill down: Entire study and associated observations

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Selected Transporter data display

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Example with Aprepitant

Filter Using “Sources”

Filter Using “Study Type”

Select specific parameters

under enzyme inhibitor

Select Parameters of Interest

Result with Filters

Source Document

Termination of Phase IIb study due to DDI

Here is an example of how a Phase IIb study

was terminated due to a drug-drug interaction

A dose modification could have prevented the termination of the

Phase IIb study

Metabolizing Enzymes &Transporters (MET) Module for PharmaPendium

Value:

Unmatched level of curation from a unique data source:

More data per drug

More experimental detail

Highest quality data

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Open Discussion and Questions

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