Population pharmacokinetics II: Estimation methods

Objective: To present, compare, and contrast the various approaches to estimating population pharmacokinetic (PPK) models with respect to the mathematical foundation, statistical aspects, software programs for implementation, and underlying assumptions. Data Sources: Information on PPK was retrieved from a MEDLINE search (1977-August 2004) of literature and a bibliographic review of review articles and books. This information is used in conjunction with experience to explain the various methodologic approaches to PPK. Study Selection and Data Extraction: All articles indentified from data sources were evaluated and relevant information was included in this review. Data Synthesis: Over 80 articles dealing with PPK estimation methods and/or their implementation were identified and reviewed. Sixty-four of these were chosen for their direct relevance to the subject of this article. Different estimation methods ranging from the naive averaging and naive pooled approaches through the standard two-stage approach to the nonlinear mixed-effects modeling approaches for estimating PPK are reviewed with their advantages and limitations. Conclusions: PPK estimation methods that rely on the characterizing of mixed (fixed and random) effects are known to produce PPK parameter estimates that are less biased than those obtained using the naive and standard two-stage approaches. The NONMEM software is the most widely used software for the characterization of PPK.