Two-stage Research Articles

The population approach to pharmacokinetic data analysis: rationale and standard data analysis methods.

Population pharmacokinetics describe the typical relationships between physiology (both normal and disease altered) and pharmacokinetics, the interindividual variability in these relationships, and their residual intraindividual variability. Knowledge of population kinetics can help one to choose initial drug dosage, to modify dosage appropriately in response to observed drug levels, to make rational decisions regarding certain aspects of drug regulation, and to investigate and elucidate certain research questions in pharmacokinetics. Experimental data from which population kinetics might be estimated often come from only those few individuals both willing and available to be studied. Clinical data from patients undergoing care might be more representative. These data, however, are marked by varying quality, accuracy, and precision, as well as there being few data per patient. Population pharmacokinetic parameters have traditionally been estimated either by fitting all individuals' data together as though there were no individual kinetic differences [the naive pooled data (NPD) approach], or by fitting each individual's data separately and then combining the individual parameter estimates [the two-stage (TS) approach]. These methods have certain theoretical problems which can only be aggravated when the deficiencies of data typical of clinical data are present. In this paper, the standard approaches are discussed and illustrated (using nondeficient data) in order to introduce subsequent papers in which alternative data analysis methods for population parameter estimation are defined, discussed, and compared.

Evaluation of methods for estimating population pharmacokinetic parameters. II. Biexponential model and experimental pharmacokinetic data.

Individual pharmacokinetic parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean-kinetics, interindividual variability, and residual variability, including intraindividual variability and measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters have been estimated either by fitting all individuals' data together as though there were no individual kinetic difference, the naive pooled data (NPD) approach, or by fitting each individuals' data separately and then combining the individual parameter estimates, the two stage (TS) approach. A third approach, NONMEM, takes a middle course between these. This study provides further evidence of NONMEM's validity by comparing, using simulation, the three approaches on three types of data sets corresponding to three typical types of pharmacokinetic studies. The estimates of population parameters provided by the NPD method are poorer than those provided by either of the other methods. The estimates provided by the TS method are adequate for mean values and for residual variability, but not for interindividual kinetic variability. NONMEM's estimates are as good as those of the TS method for mean parameters and for residual variability, and considerably better for interindividual variability. The latter estimates are still not acceptable in an absolute sense. This is probably due, not to an intrinsic fault of the method (as it is in the case of the TS approach), but to an insufficient number of individuals being studied.

A NOTE ON TWO STAGE SECOND BEST

MetroeconomicaVolume 21, Issue 1 p. 77-80 A NOTE ON TWO STAGE SECOND BEST Clarence C. Morrison, Clarence C. Morrison University of GeorgiaSearch for more papers by this author Clarence C. Morrison, Clarence C. Morrison University of GeorgiaSearch for more papers by this author First published: February 1969 https://doi.org/10.1111/j.1467-999X.1969.tb00771.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume21, Issue1February 1969Pages 77-80 RelatedInformation