Examples of population pharmacokinetic modeling in drug development using NONMEM

The population approach to pharmacokinetic analysis, and its application to the identification of patient characteristics that affect a drug\u27s pharmacokinetic parameters, is achieving greater prominence in the drug development process. Specifically, population analyses are a way to gather information that might be difficult to capture in some subpopulations. In the fall of 1997, the Food and Drug Administration proposed new legislation, commonly known as the “Pediatric Rule”. This new legislation required pharmaceutical companies to collect pediatric data for drugs with indications applicable to children before the compound would be approved. Other than conducting traditional pharmacokinetic clinical trials, another way to collect this information would be to perform a population pharmacokinetic analysis. Two different examples of this approach are presented. The first study was conducted on traditional pharmacokinetic data (intense sampling) pooled from four pediatric trials. The second study is an example of the ability of the population approach to take advantage of sparse data obtained as a secondary objective of a clinical study. A population pharmacokinetic analysis was conducted for azithromycin on data from pediatric patients enrolled in four separate clinical trials. A two compartment model with parallel zero- and first-order absorption was found to best fit the data. Potential covariates were assessed for oral clearance (CL/F), oral volume of distribution in the peripheral compartment (V2/F), intercompartmental oral clearance (Q/F), and the first-order absorption rate constant (ka). Weight was found to be a significant covariate for both CL/F and V2/F. No covariates were found to be significant for Q/F or ka. A population pharmacokinetic analysis was conducted for prednisolone on data from thoracic organ transplant patients. A one compartment model with a fixed first order rate of absorption was found to best fit the data. Potential covariates were assessed for oral clearance (CL/F) and oral volume of distribution (V/F). Sex and concomitant ciprofloxacin use were found to be significant covariates for CL/F. No covariates were found to be significant for V/F. Data was also available on plasma concentrations of prednisolone\u27s metabolite, prednisone. It was not possible to derive a robust and clinically meaningful model that incorporated the metabolite data