Population PKPD Mode.. - Pharsight Corporation

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How Can We Evaluate ? • Assumption Checking ● ● Randomization tests for the p-values Graphics for distributional assumptions (Residuals, empirical Bayesian estimates, …) • Stability/precision of parameter estimates ● ● ● ● Validation through parameter prediction errors Log-Likelihood Profile Bootstrap (parametric & non-parametric) Cross-Validation/Leverage analysis • Assessment of model performance/properties ● ● ● Prediction errors (from internal or external test set) Posterior Predictive Check/ Predictive Check/ Visual / Numerical / Quantitative Sensitivity Analysis Karlsson et al. Assumption testing in population pharmacokinetic models: illustrated with an analysis of moxonidine data from congestive heart failure patients. J PK B 26(2):207-46 1998. EI Ette. Population Model Stability and Performance. J Clin Pharmacol 37:486-495 (1997). slide 44 © Pharsight Corporation All Rights Reserved
When to use diagnostics ? ● ● ● Basic • Confirm convergence : numerical checks • Check if we had some improvement (OFV lower, BSV on parameter lower, residual variability lower…) Key runs • Unusual covariate detected : confirm with randomization test • Depends on the importance of the run Final run • Extensive diagnostics • Check if we have influential individuals ♦ Individual contributions to OFV + fits with and without the suspect individuals ♦ Case deletion diagnostics, Jackknifing • Check if we have outliers ( data with |WRES| > 4) compare fit with and without outliers • Check if parameters are precise not on a boundary and plausible ♦ Standard errors may be obtained - Asymptotically from covariance step: always symmetric may contain impossible values - From bootstrap: time consuming - From likelihood profiling : time consuming poor if LRT not applicable and if likelihood approximation is far from the true likelihood • Check if the model describe the observed data well (PPC) slide 45 © Pharsight Corporation All Rights Reserved
Page 1 and 2: Population PK/PD Modeling - The Pha
Page 3 and 4: Agenda Pharsight Company Overview R
Page 5 and 6: Who Is Pharsight? A company that he
Page 7 and 8: Who Are Pharsight Customers? This i
Page 9 and 10: Reporting and Analysis Services (RA
Page 11 and 12: RAS Value: High Quality Clinical Ph
Page 13 and 14: RAS Offers Three Analytic Competenc
Page 15 and 16: PK/PD Expertise in Early Drug Devel
Page 17 and 18: Communication Model: Single-Point C
Page 19 and 20: RAS Regulatory PK-PD Modeling RAS s
Page 21 and 22: Workflow: Population PK Analysis Pa
Page 23 and 24: QC/QA of the Analysis Dataset SAS D
Page 25 and 26: Regulatory and Timely POP PK/PD Pha
Page 27 and 28: PK Data PK from PHASE I, II and III
Page 29 and 30: Typical POP PK Model Development Wo
Page 31 and 32: Examples of GOF Plots Covariance ne
Page 33 and 34: Model Building : Adding Covariates
Page 35 and 36: Summary of Model building Absorptio
Page 37 and 38: Typical POP PK Model Development Wo
Page 39 and 40: Examples of Graphs to Aid Covariate
Page 41 and 42: Model Discrimination, Evaluation an
Page 43: What Can We Evaluate ? • The diff
Page 47 and 48: What to use in diagnostics ? ●
Page 49 and 50: Example of predictive check Drug RO
Page 51: Proprietary Notice ● All contents

Population PKPD Mode.. - Pharsight Corporation

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