Establishing Best Practices and Guidance in Population Modeling: An Experience With an Internal Population Pharmacokinetic Analysis Guidance

Abstract

RESULTSThe Pfizer Population Pharmacokinetic Analysis Guidance is included as Supplementary Appendix S1 online. The full content of the guidance and a general workflow are presented in Figure 1 and Figure 2, respectively, and general recommendations are summarized below. It should be noted that the recommendations in the guidance were based on current best practice and state of knowledge. The guidance will be updated and revised on a regular basis as new methodologies are developed and the model-building process is refined. The guidance was written with internal and external references to avoid in-depth technical and theoretical discussion within the guidance itself: the full list of references applicable to the guidance can be found in the Reference section of the Supplementary Appendix S1 online.The guidance itself does not address tool-specific implementation but is primarily focused on outlining the expected population pharmacokinetic (Pop PK) modeling-related processes and procedures that should be undertaken by the analyst. However, guidance recommendations are based on standard tools and relevant terminology, including NON-MEM (ICON Development Solutions, Ellicott City, MD), 1 Perl speaks NONMEM (PsN), 2 and Xpose. 3 Points to consider before conducting a Pop PK analysisPopulation modeling analysis plan. It is recommended that a population modeling analysis plan (PMAP) be developed to prospectively outline the modeling approach before conducting a Pop PK analysis. In addition, the PMAP should be finalized before database lock if the analysis results are to be included in a regulatory submission. A well-prepared PMAP should provide an overview of the purpose of the modeling, prior information used, the choice of studies/data to be included for analysis, the proposed modeling approach, and assumptions made. The level of detail required in the PMAP depends on the intended use of the modeling analysis, as the plan in some cases can be considered a "living document," i.e., updates to the plan can be made as more information becomes available. A PMAP should facilitate writing of the population modeling analysis report (PMAR) in a timely manner upon completion of model development and should be an effective planning tool both for the analyst and for any reviewer to assess whether the original objectives of the analysis were met. cal and statistical summaries of dependent variables and demographics, including covariates, should be completed to help with identifying potential errors. In addition, this will help to identify the base structural model and components of the statistical model, as well as potential covariate relationships and outliers.Below the limit of quantification. It is not uncommon that some concentration data are censored as below the limit of quantification (BLQ) by the bioanalytical laboratory and reported qualitatively in Pop PK data sets. Commonly used approaches for handling BLQ concentrations have been shown to introduce bias in the parameter estimates and to result in model misspecification...

dOFV distributions: a new diagnostic for the adequacy of parameter uncertainty in nonlinear mixed-effects models applied to the bootstrap

“…Given the importance of parameter uncertainty in decision-making, there is no reason why scrutiny towards uncertainty estimates should be ignored. Along with other efforts towards a standardization of model building and evaluation procedures [16], the dOFV diagnostic should be an integral part of model assessment. This is particularly true as the performance of the different methods to obtain estimates of parameter uncertainty remains unclear.…”

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

“…The predictive accuracy of the final pharmacokinetic model was examined by visual predictive checks (VPCs) (33). Visual predictive checks were performed by simulating the serum concentration-time profiles for piperacillin and tazobactam using NONMEM (version VII; Globomax LLC, Ellicott City, MD, USA).…”

Reporting a Population Pharmacokinetic–Pharmacodynamic Study: A Journal’s Perspective

“…Therefore the examples provided in this article should be viewed from a reporting/presentation perspective only, and not from a methodological perspective. For recent educational articles on basic pharmacometric techniques and practices, see references [7][8][9][10][11]. Furthermore, it is recommended that readers seek published manuscripts of pharmacometric (or related) research in their fields of interest for further examples of currently used methodologies.…”