A Compartment Model for a Sustained Release Preparation with Zero-order Release

Abstract

A compartment model with zero-order release in the gastrointestinal tract, first-order absorption to plasma and first-order elimination from plasma was examined in a series of studies on the clinical pharmacokinetics of BKU, a sustained release preparation of urapidil. The plasma levels of urapidil were measured for 24 hours after a single oral dosing of BKU to six healthy male volunteers, followed by the repeated dosing at each 12 hours for 6 days. On day 7, the plasma levels were again measured for 24 hours after a single dosing. For the expression by the formulation of this model, the reduced model wherein the absorption rate constant is equivalent to the elimination rate constant was taken into consideration to the ordinary model. The reduced model was applied to the cases in whom fitting of the ordinary model failed to apply due to no distinction in two rate constants. Time lag from dosing to initiation of zero-order release was also considered. A simplex method was used for model fitting and parameter estimation to the data of a single administration. Without consideration of time lag, the reduced model was fitted in three cases out of 6, while the ordinary model was fitted in the other 3 cases. With considera tion of time lag, the reduced model was fitted in only one case. Akaike's Information Criterion revealed that the incorporation of the time lag improved the fittings. Plasma levels of repeated dosing were simulated using the parameters estimated from the data of a single dosing and were revealed to be close to the observed levels except for one case. However, the meanings or interpretations of the estimated parameters were not necessarily valid in the model with or without time lag.