Role of PKPD Modeling and Simulation in Influencing ... - Pharsight

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Cp (ng/mL) Case Study 1: Transitioning from Preclinical to FIH Allometric scaling was used to predict human pharmacokinetics of CS-3030, an oral, direct Factor Xa inhibitor. A combination of daily doses (10 to 320mg), regimens (QD and BID), and bioavailability ranges (4.5 to 50%) was chosen to compensate for any misspecification due to projection method or underlying assumptions. F=0.045 F=0.09 F=0.18 F=0.5 0 4 8 12 20 40 80 160 Parameter Monkey Projected Human 4000 Ka 0.75 h -1 0.75 h -1 2000 V/F 7.6 L 151 L 5 10 20 0 CL/F 0.5 L/h/kg 18.2 L/h 4000 2000 Assumes F = 0.09 0 0 4 8 12 20 0 4 8 12 20 Time (Hr) S Rohatagi et al., Model based development of a direct Factor Xa inhibitor, ACoP Meeting, Tucson AZ, Mar 2008 Slide 20 © Tripos, L.P. 2011 All Rights Reserved
Case Study 1: Transitioning from Preclinical to FIH Preclinical PK/PD data from cynomolgous monkey, relative potency information and literature data were used for simulation. Similar biomarker models were assumed in monkey and human. Anti-FXa = 0.008.Cp – 0.2 PT = 1 + 0.47.(Anti-FXa) 0.8 The following criteria to determine the target dose range: • anti-FXa activity within 0.5-0.8 IU/mL range (based on enoxaparin) • 2- to 3-fold increase in PT (based on warfarin) S Rohatagi et al., Model based development of a direct Factor Xa inhibitor, ACoP Meeting, Tucson AZ, Mar 2008 Slide 21 © Tripos, L.P. 2011 All Rights Reserved
Page 1 and 2: Role of PKPD Modeling and Simulatio
Page 3 and 4: A Brief History of PK/PD THE LATE 6
Page 5 and 6: 1968: Was it a Premature Birth? •
Page 7 and 8: 1979: A Rebirth Lewis Sheiner and c
Page 9 and 10: 80’s: Toddling Growing use of PK/
Page 11 and 12: A Brief History of PK/PD THE 90’S
Page 13 and 14: 90’s: The Advent of Mechanism-Bas
Page 15 and 16: A Brief History of PK/PD PK/PD TODA
Page 17 and 18: PK/PD has Matured Technically…
Page 19: ROLE OF PK/PD MODELING AND SIMULATI
Page 23 and 24: Event Probability (%) 0 10 20 30 40
Page 25 and 26: Case Study 1: Transitioning from Pr
Page 27 and 28: Case Study 2 — Step 1: Model Diab
Page 29 and 30: Case Study 2 —Step 3: Match entry
Page 31 and 32: PERSPECTIVES Slide 31 © Tripos, L.
Page 33 and 34: Perspectives • … as well as reg
Page 35 and 36: Acknowledgements • Pharsight coll

Role of PKPD Modeling and Simulation in Influencing ... - Pharsight

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