Understanding the Why, What, When, Where and How

of Pre-clinical ADME

Luke Lightning, PhDAlquest Therapeutics

San Francisco, CAJune 28, 2012

Pre-clinical Drug Development Symposium Sponsored by Deloitte, Patheon, and QB3

Industry and Startup Perspective• Broad overview, my experiences• Why is ADME important?

– ADME assesses developability – chemistry is very good at developing potent and selective compounds (rarely the reason for late stage - more expensive- failure)

• Alquest Therapeutics (2010-present)– Virtual– Small molecule prodrugs– Neurological indications (PD, AD)– Outsource ADME work to USA and China– “ADME on a budget”

• ARYx Therapeutics (2004-2010)– Small molecules– CV, GI, neurological indications (Phase 1 and Phase 2)– Developed most ADME studies in-house, some CROs– 15-100 employees, IPO in 2007

Regulatory Considerations• Read FDA Guidances

– Decision trees– Substrates– Inhibitors– Concentrations– Next steps– etc.

• These guidances are in preparation for clinical work

• FDA DRAFT Guidance on Drug-Drug and Therapeutic-Drug Interaction Studies (February 2012)

• FDA Guidance Safety Testing of Drug Metabolites• FDA Guidance on Preclinical Safety Evaluation of Biotechnology-Derived

Pharmaceuticals

In Vitro Study Considerations• Costs are ESTIMATES per compound outsourced (averaged from 3 US-based CROs)

– Non-USA usually much cheaper • Unlimited variations in protocols are possible price differences• Typically require LC/MS/MS and bioanalytical method development

– Substrate and metabolites• Plasma protein binding (e.g. equilibrium dialysis)

• Metabolic stability• Metabolic profiling• Drug-Drug interactions• Induction

• Permeability (e.g. Caco-2)• Transporters (e.g. Pgp)

• Rodent, dog, monkey, human• Plasma/blood• Liver microsomes• Hepatocytes• Purified enzymes

(~$5000)

(~$10000)

(~$25000)

(~$25000)

($10000)

(~$2000)

(~$5000)

(~$5000)

In Vivo Study Considerations• Unlimited variations in protocols are possible price differences• Require:

– LC/MS/MS capabilities, bioanalytical method development (~$10000)– Dose formulation studies (~$20000)– Some type of software package for analysis (not inexpensive)

• GastroPLUS• Cloe PK• PK-Sim• SimCYP• WinNonlin/Phoenix or• Watson LIMS

• Pharmacokinetics– Determination of PK Parameters– Tissue distribution

Mouse, Rat, Dog, MonkeyMultiple animals, doses, time pointsIV, IP, oral gavageBlood, urine, bile, feces

(~$4000-8000)

In House Preclinical Study Considerations

• Granting Agency Restrictions• Personnel

– Hiring costs, specialized– Contractors, interns for lab work

• GS-ICE at UCSF• InternMatch

• Equipment , Supplies, and Software Costs– Purchase used equipment

• BioSurplus • LabX

– Share equipment• QB3/Fibrogen garages • Bioscience Laboratories • CPMC-RI

– Vivarium and/or kennel setup and maintenance

$$$$

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Outsourced Preclinical Study Considerations

• Contract Research Organizations (CROs)– Loss of direct oversight, but no hiring costs– Robot vs. Human (no alterations)– Turnaround time (week-month)– USA vs. non-USA (cost, granting agencies, quality?)– Specialized vs. “One Stop Shops”

• Integrated Analytical Solutions (LC/MS/MS), MuriGenics (animal PK), Optivia Biotechnology (transporters)

• BD Biosciences, Invitrogen, Xenotech (ADME services)• Charles River, Covance, Ricerca Biosciences (discovery clinical trials)

– Searchable Databases:• Assay Depot • Science Exchange

ADME Work Plan Example• Exploratory experiments (non-GLP)

– To get a quick idea of ADME profile and help select leads from efficacy studies– 10 compounds for in vitro experiments (singlet)

• Plasma protein binding and blood stability• In vitro metabolic stability in liver microsomes

– 2-3 compounds for rodent PK experiments• IV, oral, tissue distribution?

– 2-3 compounds for CYP3A4 inhibition experiments– Evaluation of compounds and efficacy studies– Repeat?

• 2-3 candidates for more in-depth ADME analysis– In vitro and in vivo experiments run in triplicate– Substrates and metabolites

Preclinical(ADME)

5000

1**BioTech Primer, Inc., 2011; Nature Reviews/Drug Discovery, December 2009

Summary and Future Directions• ADME is your BFF!

– Learn more about your candidates – Can aid in go no-go decisions

• Several in vitro and in vivo approaches are available– Stability, drug interactions and induction, transporters, PK

• Multiple factors should be considered before performing ADME experiments in-house or through outsourcing – Financial, granting agencies, personnel, equipment– Negotiate with vendors, unlimited variations possible

• FDA documents serve as excellent references for planning and executing ADME experiments

• Some potential future directions for ADME:– RapidFire mass spectrometry – Humanized mice – HepatoPac platform – More preliminary in silico experiments

Thank you! Questions?

Contact Info:Luke Lightning, PhD

Alquest TherapeuticsEmail: llightning@alquest.us

Twitter: @lukelightningLinkedIn: http://www.linkedin.com/in/lukelightning

Bay Area LifeTech Happy Hour on July 12 in SFhttp://www.meetup.com/BayAreaLifeTech/

Very Handy Reference Book: Khojasteh, et. al. DMPK Quick Guide, 2011Searchable Discussion Board: http://www.pharmpk.com/