Pfizer VP Discusses Role of Modeling and Simulation in Drug Discovery and Development

Joseph C. Fleishaker Vice President Clinical Research Pfizer

The Outline ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Why M&S? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Everybody brings their own model

The trick – using one model ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Source: J.E. Dumont, Cross Signaling, Cell Specificity, and Physiology Am. J. Physiology, Cell. Physiology . Vol. 283, Issue 1, C2-C28, July 2002

Critical nodes in signaling pathways: insights into insulin action – 2006 Cullen M. Taniguchi, Brice Emanuelli and C. Ronald Kahn NATURE REVIEWS MOLECULAR CELL BIOLOGY FEBRUARY 2006

Assessing the Impact of Predictive Biosimulation on Drug Discovery and Development Journal of Bioinformatics and Computational Chemistry Author: S. Michelson vol 1 (1): 169-177

The Roles of Cells and Mediators in a Computer Model of Chronic Asthma International Archives of Allergy Immunology Author: A.K. Lewis, T. Paterson, C.C. Leong, N. Defranoux, S.T. Holgate, C.L. Stokes Vol. 124:282-286

Uses of M&S for Target Selection ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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Structural Interaction Fingerprints – Uses for Modeling and Simulation Target-focused Virtual Library generation J. Med. Chem.; 2006; 49(2); 490-500

Calculated HLM CLint Measured HLM CLint ,[object Object],[object Object],In Silico Model for HLM has been Useful in the Design of Program X Analogs ,[object Object],[object Object],[object Object],[object Object],In training set

M&S in Compound Selection ,[object Object],[object Object],[object Object],[object Object]

PK – SimCyp ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

M&S PK ,[object Object],[object Object],[object Object]

Estimating Dose-Response in Humans Using Pre-Clinical Data Experience with Gabapentin, Pregabalin and Related Compounds (Lockwood et al. Pharm Res 2003;20:1752-9) ,[object Object],[object Object],[object Object],[object Object],[object Object]

Step 1 : Estimate Relative Potency of Pregabalin and Gabapentin UNCERTAINTY in Potency Ratio Estimate Range = 2-4, best guess = 3 Pre-Clinical Data gabapentin/pregabalin EC 50 ED 50 ,[object Object],[object Object]

Assumption: Similar Concentration-Response Shape PK from Phase 1 ,[object Object],[object Object],Baseline pain score Placebo effect Drug effect

What Can We Do With This Model? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Improvement from placebo 0 200 400 600 800 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 Distribution of Model Predicted Trial Outcomes 0.05 0.1 0.2 0.5 0.8 0.9 0.95 Pregabalin dose (mg/day)

Improvement from placebo 0 200 400 600 800 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 Actual Trial Results and Predicted Outcome Distribution 0.05 0.1 0.2 0.5 0.8 0.9 0.95 Pregabalin dose (mg/day)

M&S PK/PD - Impact on Drug Development ,[object Object],[object Object],[object Object]

Combining diverse data to obtain overall view of drug value

Clinical Utility Index (CUI) ,[object Object],[object Object],[object Object],[object Object],Ouellet et al.,Clinical Pharmacology & Therapeutics (2009); 85 , 3, 277–282

Hybrid Conjoint Model Low High Size of bubble reflects relative importance based on hybrid conjoint. Efficacy Safety/Side Effect * Ouellet et al.,Clinical Pharmacology & Therapeutics (2009); 85 , 3, 277–282 High Low

[object Object],Calculation of CUI Ouellet et al.,Clinical Pharmacology & Therapeutics (2009); 85 , 3, 277–282 CUI - Attribute Clinical Diff Weight Residual Effect (LEEDS) 5 points 35% WASO 25 min 25% Quality 20 points 17% LPS 15 min 13% Sleep Architecture (Stage 1, Stage 3-4) 5% 10%

Median CUI and 80% CI Ouellet et al.,Clinical Pharmacology & Therapeutics (2009); 85 , 3, 277–282

PD-200390 vs PD-299685 Ouellet et al.,Clinical Pharmacology & Therapeutics (2009); 85 , 3, 277–282

M&S in Commercial Assessment ,[object Object],[object Object]

Conclusions ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Pfizer VP Discusses Role of Modeling and Simulation in Drug Discovery and Development

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Pfizer VP Discusses Role of Modeling and Simulation in Drug Discovery and Development

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