Joseph Kim, PhD, RPh Director Clinical Pharmacology Modeling & Simulation

1. Use of Pharmacokinetics Modeling & Simulation in the Drug Development: From Discovery to Development Joseph Kim, PhD, RPh Director Clinical Pharmacology Modeling & Simulation GSK, R&D, Research Triangle Park

2. 12–15 yearsin development One out of5,000 to 10,000compounds makesit to patients >$1 billionper drug 7 out of 10 drugsdon’t cover averageR&D costs Discovery (2–10 years) Pre-clinical Testing Phase I Phase II Phase III Agency Review / Approval 0 2 4 6 8 10 12 14 16 Years High risk R&D investment

3. Drug development process is finding answers to many questions Can we get the optimal dose from the POC trial? Interactions? What is the optimal patient population? Dose schedule? What is the 1st indication? Safe in animal model? Discovery POC Dose Selection Approval Trials PLE FTiH Combination Product? What’s the probability of Phase III success? Effective in animal model? Do we need a new formulation? Do we cease development? How do we beat the competition? Biomarker α Endpoint? Slide from Jeff Wald, GSK

4. Evolution of benefits and risks:Challenges and opportunities SAFETY- RARE SAFETY- FREQUENT EFFICACY At any point in development, there is a need to be able to evaluate whether the realized or anticipated benefits outweigh the potential risks 1 KNOWLEDGE (Certainty) 0 IND PHASE 1 NDA PHASE 3 MARKET PHASE 2 Discovery PRECLINICAL DEVELOPMENT Bob Powell, ISPOR 2008

5. Clinical Pharmacology: Study of drug in humans* • Pharmacokinetics • Pharmacodynamics • Drug Metabolism and Transport • Optimizing and Evaluating Patient Therapy • Drug Discovery and Development *Principles of Clinical Pharmacology, 2nd Ed. Arthur Adkison et al.

6. [Drug] Time Biomarker Toxicity [Drug] What is Pharmacokinetics • What does the body do to drugs • Absorption • Distribution • Metabolism • Elimination Pharmacodynamics: What does the drug do to the body

7. PK Use in Drug Development • Discovery (pre-clinical) • Phase I – First Time in Human study (FTiH) • Phase I – Non- FTiH study • Phase II – Proof of Concept, Proof of Mechanism, Dose Finding study • Phase III – Pivotal studies • Phase IV – Post approval commitment, PLE(Product Line Extension), Country specific registrations

8. PK Use in Drug Development • Discovery (pre-clinical) • Allometric scaling> Modeling & Simulation • Predict AUC, Cmax, target dose • Suggest dose strength • Compare human exposure to animal toxicity (NOAEL- No Observed Adverse Effect Level)

9. Case #1: Use of Modeling & Simulation with Animal toxicokinetic study • Single dose rat study – no toxicity but some unusual TK profile • Repeat dose rat study initiated – animal dies with 1500mg/kg dose after 3-4 days • Single dose study TK profile reviewed and re-evaluated using modeling & simulation

10. Case #1– Rat Single Dose Data

11. Snapshot of 300 mg/kg Dose for SD and Repeat Dose • Significant accumulation, 4 fold increase in AUClast • Elimination phase has not begun at 24 hrs. on neither day 1 or day 7

12. Nonparametric superposition prediction – 1500mg QD, assuming t1/2 is 24 hrs starting 48hr after single dose

13. PK Use in Drug Development • Phase I – First Time in Human study (FTiH) • Single Dose Study>> Dose escalation • Repeat Dose Study>> Dose escalation • PK data analysis and Modeling & Simulation • Predict AUC, Cmax, target dose • Compare human exposure to animal toxicity (NOAEL- No Observed Adverse Effect Level) or biological activity (MABEL – Minimum Anticipated Biological Effect Level)

14. PK Use in Drug Development • Phase I – After FTiH • Formulation study • Food effect study • Drug Interaction study (perpetrator vs victim) • Renal impairment study • Hepatic impairment study • QTc study • Others (pediatric, elderly population) • Compare human exposure to animal toxicity (NOAEL- No Observed Adverse Effect Level)

15. PK Use in Drug Development • Phase II – Proof of Concept, Proof of Mechanism, Dose Finding study • Modeling & Simulation • Predict target site concentration and needed dose • Use protein binding, receptor occupancy etc. • Suggest dose and regimen for Phase III • Prepare EoP2a meeting with regulatory agency • Predict probability of success with given dose and variability • Compare human exposure to animal toxicity (NOAEL- No Observed Adverse Effect Level)

16. Case #2Phase IIa (POC): Confirming Biologic Activity Dose-Response Exposure-Response Some numbers were modified for confidentiality

17. PK Use in Drug Development • Phase III – Pivotal studies • Population PK and Modeling & Simulation • Adaptive Design • Ethnopharmacology • Pharmacogenetics • Regulatory filings

18. Case #3Phase II/III: Adaptive Design Dose Selection Patient is randomised in blinded fashion to: placebo (25%), high dose (25%) or “optimal” dose (50%) [5, 15, 30, 60, 120, 180]mg 2 4 STOP for Futility Continue Stop Go 1 5 Continual Reassessment Method chooses the “optimal” dose that will optimise learning about the ED50 STOP for Efficacy 6 , Slide from Alun Bedding

19. PK Use in Drug Development • Phase IV – Post approval commitment, PLE, and Country specific registrations • Population PK and Modeling & Simulation • Bioequivalence study • Foreign country registration • Regulatory filings

20. A model-based continuum provides a quantitative framework for the expected…and unexpected questions LB Sheiner, Clinical Pharmacology and Therapeutics, March 1997 Lalonde, et al., Clinical Pharmacology and Therapeutics, July 2007

21. Summary • Drug Development is very high-risk business with big uncertainty and variability • Public and FDA ask more efficient way of Drug Development • PK/PD modeling and simulation can answer many questions in every stage of Drug Development • Model-based drug development/adaptive design approaches are powerful tools to improve clinical drug development, regulatory guidance and the quality of NDA submissions • USA FDA is aware and willing to accept innovations in New Drug Development Processes • Choosing the right dose is extremely important

22. Acknowledgements and References • GSK R&D Colleagues-- Jeff Wald, Patrick Ryan, Alun Bedding • Bob Powell (formerly at FDA)