Methods to Account for Inaccuracies in the Dosing History When Performing Population Pharmacokinetic Analysis

Purpose  To develop and assess methods to account for missing dose history (MDH). Methods  A simulation study was performed with different doses, dose times and formulations using NONMEM. Four methods were used to account for MDH, these were the ideal dose method (IDM) which uses the actual dose history, the concentration minimum method (CMM) which assumes that the nominal dose history is accurate, the extrapolation subtraction method (ESM) which estimates the residual concentration at the time of the study dose and the concentration time method (CTM) where the time of the previous dose event is estimated. The CTM is a new method. Results  The CTM was superior to ESM and CMM and provided parameter estimates that were comparable in accuracy to the IDM. Conclusions  When the nominal dosing history is available then the CTM is a simple and effective method to account for potential inaccuracies in the dose history.