Luke Lightning, ADME DMPK PKPD startups FDA

1. Pre-clinical Drug Development Symposium Sponsored by Deloitte, Patheon, and QB3
Understanding the
Why, What, When, Where and How
of Pre-clinical ADME
Luke Lightning, PhD
Alquest Therapeutics
San Francisco, CA
June 28, 2012

2. 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

3. 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• FDA DRAFT Guidance on Drug-Drug and Therapeutic-Drug Interaction Studies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

4. 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 (~$5000)
– Substrate and metabolites
• Plasma protein binding (e.g. equilibrium dialysis) (~$5000)
• Metabolic stability (~$5000) • Rodent, dog, monkey, human
• Metabolic profiling (~$10000) • Plasma/blood
• Drug-Drug interactions (~$25000) • Liver microsomes
• Hepatocytes
• Induction (~$25000)
• Purified enzymes
• Permeability (e.g. Caco-2) ($10000)
• Transporters (e.g. Pgp) (~$2000)

5. 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 (~$4000-8000) Mouse, Rat, Dog, Monkey
– Determination of PK Parameters Multiple animals, doses, time points
– Tissue distribution IV, IP, oral gavage
Blood, urine, bile, feces

6. 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 $$$$

7. 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

8. 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) 5000
• 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?
Preclinical
(ADME)
• 2-3 candidates for more in-depth ADME analysis
– In vitro and in vivo experiments run in triplicate
– Substrates and metabolites 1*
*BioTech Primer, Inc., 2011; Nature Reviews/Drug
Discovery, December 2009

9. 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

10. Thank you!
Questions?
Contact Info:
Luke Lightning, PhD
Alquest Therapeutics
Email: llightning@alquest.us
Twitter: @lukelightning
LinkedIn: http://www.linkedin.com/in/lukelightning
Bay Area LifeTech Happy Hour on July 12 in SF
http://www.meetup.com/BayAreaLifeTech/
Very Handy Reference Book: Khojasteh, et. al. DMPK Quick Guide, 2011
Searchable Discussion Board: http://www.pharmpk.com/