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 100 mg 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.

Efficacy and safety evaluation of Allisartan Isoproxil in patients with hypertension: a meta-analysis

“…The lack of statistical significance in AE occurrence may be attributed to the relatively small sample sizes in the studies. It is noteworthy that only 14% of oral losartan doses are converted to EXP3174 by CYP2C9 and CYP3A4, and other metabolites may potentially lead to side effects and toxicity ( 53 ). However, Allisartan Isoproxil is meticulously formulated as an esterified prodrug, and its metabolism does not involve any cytochrome P450 subfamilies ( 54 ).…”

The [13C]octanoic acid breath test for gastric emptying quantification: A focus on nutrition and modeling

“…Typically, to model digestion, the stomach is considered a continuously stirred tank reactor (CSTR), and usually represented as a first‐order ordinary differential equations (ODE), with the small intestine modeled as a plug flow reactor (PFR), modeled using partial differential equations (PDE). Since these models are usually to simulate the dosage of nutrients or drugs and their absorption, they have tended to simplify many issues that are important in digestion, such as meal properties and interactions and feedback loops within the body (Karatza & Karalis, 2020). Effects such as meal viscosity (Marciani et al, 2001), and feedback mechanisms that respond to meal compositions (Brener et al, 1983), have long been known, but have not been rigorously studied within [ 13 C]‐OABT results.…”

“…To demonstrate the model on PK applications, the same research group (Ogungbenro et al, 2015) extended the model by focusing on the double‐peaked profile phenomenon due to GE, based on the application of a gastric‐modifying drug known as Levodopa. Many related approaches have been explored in the literature, focusing on drug and nutrient distributions in plasma (Bermejo et al, 2020; Hens & Bolger, 2019; Karatza & Karalis, 2020).…”

Impact of angiotensin-receptor blockers on intrarenal renin-angiotensin system activity in hypertension: A PK/PD modelling study

“…Instead, a PK model describing Losartan and its metabolite EXP3174 is desirable, as it can be coupled to our previous RAS model (Smith and Layton, 2023) via the drug's known AT1R binding properties. Such a model has previously been developed to study gastric emptying in humans (Karatza and Karalis, 2020). However, that model simulates a single oral dose of the drug (not continuous treatment with Losartan), and does not consider the kidney as a separate compartment (thus not appropriate for studying intrarenal RAS) .…”