lightning deloitte patheon qb3 talk 2012
DESCRIPTION
Luke Lightning, ADME DMPK PKPD startups FDATRANSCRIPT
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• FDA DRAFT Guidance on Drug-Drug and Therapeutic-Drug Interaction Studies (February 2012)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: [email protected]
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/