Novel approach to bioequivalence assessment based on physiologically motivated model.

The study was conducted to exemplify an approach capable of obtaining a new insight into bioequivalence (BE) assessment, by the use of a physiologically motivated model. Data from an oral BE study of two piroxicam (PXM) products was used as an example. The BE study was carried out with 24 healthy European subjects according to a two-sequence crossover-randomized design. The test and reference formulations were a PXM generic formulation (LaborMed Pharma, Romania) and Feldene (Pfizer, USA), respectively. Plasma concentrations of PXM were monitored by a validated high-performance liquid chromatography over a period of 144 h after administration. After the structure of the optimal model was selected, parameters that characterized the whole-body disposition behavior of PXM in the subjects were derived. The paired Student's t-test and Wilkoxon's test were performed on the derived parameters. The null hypothesis of no differences in the parameters of the whole-body disposition behavior of PXM related to the test and reference product was not rejected at 5% level of significance. This result suggested that the compared products were bioequivalent and could be used interchangeably in clinical setting. The presented approach might show a new way, worth incorporating in future BE guidelines.

Computer controlled sequential simulation method: reconsidering evaluation of measurements from frequently sampled intravenous glucose tolerance test.

This work describes quantification of regulatory mechanisms glucose-insulin, using data from a frequently sampled intravenous glucose tolerance test (FSIVGTT) and a mechanistically motivated model with time delays. FSIVGTT was performed on 14 young healthy volunteers. The constructed model computationally takes into account the form of the short-time glucose infusion used. Estimated model parameters are used to derive relationships quantifying the following mechanisms of regulatory systems glucose-insulin of the volunteers enrolled: (1) glucose uptake by body cells; (2) cessation (suppression) of glucose output from liver; (3) glucose clearance. The model presented correctly approximates initial peaks and subsequent waves in plasma glucose concentration-time profiles after the glucose infusion. These results indicate that the model presented is an appropriate tool for assessing glucose behavior during a FSIVGTT.

Physiologically motivated time-delay model to account for mechanisms underlying enterohepatic circulation of piroxicam in human beings.

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.

Estimation of influence of gastric emptying on shape of glucose concentration-time profile measured in oral glucose tolerance test.

AIMS: To develop a model for simulations of processes in the oral glucose tolerance test (OGTT), using tools of the theory of dynamic systems. METHODS: Frequent sampling OGTT was performed in 13 healthy subjects (6 males and 7 females). Subsequently, employing glucose and insulin concentration-time profiles of the subjects, the model was developed. RESULTS: In all subjects the model was able to simulate influences of the insulin plasma concentration and gastric emptying rate on glucose concentration and to determine time profiles of glucose fractions retained in stomach. CONCLUSIONS: The approach presented represents an opportunity for building models for data analyses in OGTT.