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

Abstract

Losartan presents multiple peaks in the concentration-time profile. This characteristic can be attributed to gastric emptying, which is known to significantly affect the disposition of highly soluble and permeable compounds. The aim of this study was to develop a population pharmacokinetic model for losartan and its active metabolite (EXP-3174) in order to describe the effect of gastric emptying on their disposition. Population pharmacokinetic analysis was performed using concentration-time data derived from a crossover bioequivalence study in 31 volunteers after a single oral dose of 100mg losartan potassium in the fasted state. Delay differential equations (DDEs) were explored for the description of losartan absorption and EXP-3174 formation, since when solved they result in oscillatory behaviour. A two-compartment model preceded by a pre-absorption compartment (referring to small intestine) adequately described the observed concentration-time profiles of losartan. In the final model, a sinusoidal equation was used for the description of gastric emptying in view of its simplicity, leading to enhanced stability of the model and its capacity to describe periodicity. In case of EXP-3174, a one-compartment model, with a delayed first-order formation rate from losartan's central compartment, best described its disposition. Using the model developed, it was shown through simulations that changes in gastric emptying parameters lead to changes in the C-t profiles of both compounds. In particular, plasma oscillations can be enhanced or completely suppressed, simply by changing parameters affecting gastric emptying.