BOOTSTRAPPING FOR PHARMACOKINETIC MODELS - VISUALIZATION OF PREDICTIVE AND PARAMETER UNCERTAINTY

Purpose. We explore use of ''bootstrapping'' methods to obtain a measu re of reliability of predictions made in part from fits of individual drug level data with a pharmacokinetic (PK) model, and to help clarify parameter identifiability for such models. Methods. Simulation studie s use four sets (A-D) of drug concentration data obtained following a single oral dose. Each set is fit with a two compartment PK model, and the ''bootstrap'' is employed to examine the potential predictive var iation in estimates of parameter sets. This yields an empirical distri bution of plausible steady state (SS) drug concentration predictions t hat can be used to form a confidence interval for a prediction. Result s. A distinct, narrow confidence region in parameter space is identifi ed for subjects A and B. The bootstrapped sets have a relatively large coefficient of variation (CV) (35-90% for A), yet the corresponding S S drug levels are tightly clustered (CVs only 2-9%). The results for C and D are dramatically different. The CVs for both the parameters and predicted drug levels are larger by a factor of 5 and more. The resul ts reveal that the original data for C and D, but not A and B, can be represented by at least two different PK model manifestations, yet onl y one provides reliable predictions. Conclusions. The insights gained can facilitate making decisions about parameter identifiability. In pa rticular, the results for C and D have important implications for the degree of implicit overparameterization that may exist in the PK model . In cases where the data support only a single model manifestation, t he ''bootstrap'' method provides information needed to form a confiden ce interval for a prediction.