Issues in the Estimation of Time to Steady State
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*Deborah Lorah Panebianco, Merck & Co. Inc. 

Keywords: pharmacokinetics, steady state, nonlinear mixed effects modeling, effective rate of drug accumulation

If a drug accumulates during repeat dosing, then the time it takes for plasma concentrations to reach steady state is a key component of the drug’s pharmacokinetic profile. An estimate of the time to steady state is needed for regulatory labeling purposes and for validation of some clinical trial designs. The talk focuses on two estimation methods, assuming linear kinetics, which utilize PK data readily available from an early Phase I study. The AUC accumulation ratio can be used to calculate subjects' effective rate of drug accumulation, and, hence, time to steady state. Under the same assumptions, nonlinear mixed effects modeling of trough plasma concentrations can be used to obtain individual and population estimates of time to steady state. While the AUC approach is attractive in its simplicity, population estimates obtained using trough concentrations have less bias.