The Annals of Pharmacotherapy ■ 2004 November, Volume 38 ■ 1907 P opulation pharmacokinetic (PPK) models have a wide range of application both to direct patient care and drug development. There are several advantages to em- ploying PPK models compared with traditional pharma- cokinetic model development. The previous installment of this series addressed the types of conceptual models neces- sary for an understanding of PPK. 1 The current installment explains the various methods used to estimate PPK models. Over the past two and half decades, a variety of methods have been proposed for the characterization of the PPK of drugs. A discussion of some of the methods follows and is the focus of this section. The goals of a PPK analysis and the data type will determine the method selected for the analysis. Methods Applied to Population Pharmacokinetic Modeling NAÏVE AVERAGE DATA APPROACH It is common practice in preclinical and clinical pharma- cokinetics to perform studies in which the drug administra- tion and sampling schedules are identical for all subjects. For this type of analysis, there are as many data points as there are individuals at each sampling time. Analysis of such data using the naïve averaging of data (NAD) ap- proach consists of the following procedure. (1) Computing the average value of the data for each sampling time: N ¯ y i = 1/N Σ y ij Eq. 1 j = 1 for i = 1,…., n where n is the standard number of individu- al data. The averaging of data across individuals makes sense, because all y ij for j = 1, …, N have been measured under identical conditions. Population Pharmacokinetics II: Estimation Methods Ene I Ette and Paul J Williams www.theannals.com Pharmacokinetics Author information provided at the end of the text. 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 naïve averaging and naïve 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 naïve and standard two-stage approaches. The NONMEM software is the most widely used software for the characterization of PPK. KEY WORDS: estimation, pharmacokinetics, population. Ann Pharmacother 2004;38:1907-15. Published Online, 14 Sept 2004, www.theannals.com, DOI 10.1345/aph.1E259 See also Part I (2004;38:1702-6, DOI 10.1345/aph.1D374) by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from