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

Abstract

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 concentrationtime 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.Numerous drugs and other foreign substances undergo extensive elimination via bile in an unchanged or conjugated form and are available for re-absorption in the gastrointestinal tract. This is a multistep and erratic process under the control of many factors, which is referred to as enterohepatic circulation (EHC). EHC prolongs not only time required for the substance to be irreversibly eliminated from the body but also substance effects. In most cases, EHC yields to multiple peaks in plasma drug concentration-time profiles. The occurrence of multiple peaks in plasma drug concentrationtime profiles is also called 'a saw-tooth effect' [1,2]. During the past decades, extensive efforts have been made to enhance the understanding of the complicated process of EHC, using various theoretical approaches and mathematical models, as reviewed recently [3]. As a result, today there are a number of models describing behaviour of drugs possessing EHC, but models capable of estimating time delays in dynamic processes involved in EHC are missing. Therefore, this work was aimed at extending the scope of the previously published model by introducing the time-delay parameter in the EHC process.Piroxicam, a member of the oxicam group of non-steroidal anti-inflammatory drugs [4], is known under various trade names, for example, Apo-Piroxicam, Feldene, Novo-Pirocam, Nu-Pirox, Proxalyoc or PMS-piroxicam. It is recognized fo...

Novel approach to bioequivalence assessment based on physiologically motivated model

“…In order to increase paper readability, brief expla- nations are given here: (1) "the system gain". The system gain is the ratio of the output and input of the system when the system approaches steady-state (Kailath, 1980;Dedík, 1997, 2005;Dedík andĎurišová, 2004Dedík andĎurišová, , 2008Dedík et al, 2007;Tvrdonova et al, 2008); 2) "the time-delay parameter". Influences of time-delay parameters are known as time-lags in the pharmacokinetic literature (Nerella et al, 1993); (3)"physiologically motivated".…”

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“…The approach presented was designed from viewpoints of the theory linear time-invariant dynamic systems (Kailath, 1980;Dedík, 1997, 2005;Dedík andĎurišová, 2004Dedík andĎurišová, , 2008Dedík et al, 2007;Tvrdonova et al, 2008) and physiologically motivated models (Andersen et al, 2006;Tvrdonova et al, 2008). In this study, a dynamic system is considered a means of describing how one state of a dynamic process develops into another state over the course of time.…”

Physiologically Based Structure of Mean Residence Time

“…The structural components relate directly to the drug transport to the blood circulation through the following subsystems: the cardiopulmonary subsystem H cp [18], the corresponding structural component is F cp , the portal-venous subsystem H p [19], the corresponding structural component is F p , the hepatic-portal subsystem H h [20], the corresponding structural component is F h , the subsystem H o describing drug disposition in noneliminating tissues [21], the corresponding structural component is F o , the subsystem H r , if the drug is subject to the enterohepatic cycling (EHC), for example, [22, 23], the corresponding structural component is F r .…”

Modelling gastric emptying: A pharmacokinetic model simultaneously describing distribution of losartan and its active metabolite EXP‐3174

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