Pre-clinical Drug Development Symposium Sponsored by Deloitte, Patheon, and QB3             Understanding the      Why, Wh...
Industry and Startup Perspective• Broad overview, my experiences• Why is ADME important?   – ADME assesses developability ...
Regulatory Considerations• Read FDA Guidances    –   Decision trees    –   Substrates    –   Inhibitors    –   Concentrati...
In Vitro Study Considerations• Costs are ESTIMATES per compound outsourced (averaged from 3 US-based CROs)   – Non-USA usu...
In Vivo Study Considerations• Unlimited variations in protocols are possible  price differences• Require:   – LC/MS/MS ca...
In House Preclinical Study                  Considerations                         $$$$• Granting Agency Restrictions• Per...
Outsourced Preclinical Study               Considerations• Contract Research Organizations (CROs)   –   Loss of direct ove...
ADME Work Plan Example• Exploratory experiments (non-GLP)   – To get a quick idea of ADME profile and help select leads fr...
Summary and Future Directions• ADME is your BFF!    – Learn more about your candidates    – Can aid in go no-go decisions•...
Thank you!                       Questions?                        Contact Info:                         Luke Lightning, P...
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Lightning Deloitte Patheon QB3 Talk 2012

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Luke Lightning, ADME DMPK PKPD startups FDA

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Lightning Deloitte Patheon QB3 Talk 2012

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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/

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