Lightning Deloitte Patheon QB3 Talk 2012

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Luke Lightning, ADME DMPK PKPD startups FDA

Luke Lightning, ADME DMPK PKPD startups FDA

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  • ADME screening has reduced late-stage drug attrition would be helpful (i.e. why screening ADME is worth the money).  Something like "chemistry has gotten really good at optimizing potency and selectivity, but rarely are those two parameters a reason for clinical (i.e. more expensive) failure. ADME assesses HUMAN developability." or something like that.
  • IAS is about ready to launch GLP


  • 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Substrates – Inhibitors – Concentrations – Next steps – etc.• These guidances are in preparation for clinical work• FDA DRAFT Guidance on Drug-Drug and Therapeutic-Drug Interaction Studies (February 2012)• FDA Guidance Safety Testing of Drug Metabolites• FDA Guidance on Preclinical Safety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: Twitter: @lukelightning LinkedIn: Bay Area LifeTech Happy Hour on July 12 in SF Handy Reference Book: Khojasteh, et. al. DMPK Quick Guide, 2011 Searchable Discussion Board: