Physiologically Motivated Time‐Delay Model to Account for Mechanisms Underlying Enterohepatic Circulation of Piroxicam in Human Beings

Abstract

The study was conducted to formulate a physiologically motivated time-delay (PM TD) mathematical model for human beings, which incorporates disintegration of a drug formulation, dissolution, discontinuous gastric emptying and enterohepatic circulation (EHC) of a drug. Piroxicam, administered to 24 European, healthy individuals in 20 mg capsules Feldene Pfizer, was used as a model drug. Plasma was analysed for piroxicam by a validated high-performance liquid chromatography method. The PM TD mathematical model was developed using measured plasma piroxicam concentration-time profiles of the individuals and tools of a computationally efficient mathematical analysis and modeling, based on the theory of linear dynamic systems. The constructed model was capable of (i) quantifying different fractions of the piroxicam dose sequentially disposable for absorption and (ii) estimating time delays between time when the piroxicam dose reaches stomach and time when individual of fractions of the piroxicam dose is disposable for absorption. The model verification was performed through a formal proof, based on comparisons of observed and model-predicted plasma piroxicam concentration-time profiles. The model verification showed an adequate model performance and agreement between the compared profiles. Accordingly, it confirmed that the developed model was an appropriate representative of the piroxicam fate in the individuals enrolled. The presented model provides valuable information on factors that control dynamic mechanisms of EHC, that is, information unobtainable with the models proposed for the EHC analysis previously.