Communicating the Value of Pharmacodynamic Modelling in Drug ...

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These results justified a safety analysis by liver enzymes that confirmed the risk in patient with elevated LFTs MBC patients treated at 100 mg/m 2 (Taxotere Package Insert) Side effects Febrile neutropenia Infection (grade 3-4) Stomatitis (grade 3-4) Toxic death Normal (n=730) 2.4 % 7.1 % 7.8 % 2.6 % Elevated (n=18) 8.6 % 33 % 39 % 17 % ODAC recommended approval in patients with normal LFTs without waiting for Phase III results. Patients with elevated LFTs were excluded from Phase III studies. MBC = metastatic breast cancer; ODAC = Oncology Drugs Advisory Committee to US FDA slide 24 30 May 2008, ARCS © Pharsight Corporation All Rights Reserved
Contribution of this approach to first approval in metastatic breast cancer “Taxotere: … the value of nonlinear mixed effects modeling of dose–PK–PD relationships… was demonstrated… PK/PD analysis identified patients at risk for neutropenia, and justified the subsequent safety re-analysis of the clinical database to address questions posed by… regulatory authorities, that allowed the sponsor to confirm the profile of the drug without waiting for Phase 3 data… population PK/PD studies provided many advantages including: ● A scientific and clinical basis by which safety concerns were alleviated… ● Accelerated approval of the drug for market access. ● Provision of key information in the package insert.” Source: Lesko et al. Eur. J. Pharm. Sci. 10, iv-xiv, 2000 slide 25 30 May 2008, ARCS © Pharsight Corporation All Rights Reserved
Page 1 and 2: Communicating the Value of Pharmaco
Page 3 and 4: FDA Perspective There is a clear em
Page 5 and 6: …. And What Can Be Done About It?
Page 7 and 8: Examples of Applications of MBDD Hi
Page 9 and 10: PK/PD applications in MBDD ● Mid-
Page 11 and 12: To simulate drug development scenar
Page 13 and 14: Public-Source Data ● Public-sourc
Page 15 and 16: Case Studies Example 1. How can pre
Page 17 and 18: Comparisons across regimens and dru
Page 19 and 20: Example 2: How can M&S be used to s
Page 21 and 22: Docetaxel model Side effects Dose E
Page 23: There was a clinically meaningful i
Page 27 and 28: Strategy: Efficient Model-Based Dev
Page 29 and 30: Results: The Model Described Mono-
Page 31 and 32: Summary of process so far …. Pre-
Page 33 and 34: Models provide answers to important
Page 35 and 36: Our purpose is to view and query mo
Page 37 and 38: Q1: What is the probability that ge
Page 39 and 40: Q2: What is the probability that, i
Page 41 and 42: Q3: Given the magnitude of LDL-C lo
Page 43 and 44: Value of MBDD approach for gemcaben

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