A Strategy for Assessing Potential Drug-Drug Interactions of a Concomitant Agent against a Drug Absorbed via an Intestinal Transporter in Humans

Abstract

A strategy for assessing potential drug-drug interactions (DDIs) based on a simulated intestinal concentration is described. The proposed prediction method was applied to the DDI assessment of luseogliflozin, a novel antidiabetic drug, against miglitol absorbed via the intestinal sodium-glucose cotransporter 1 (SGLT1). The method involves four steps: collection of physicochemical and pharmacokinetic parameters of luseogliflozin for use in a computer simulation; evaluation of the validity of these parameters by verifying the goodness of fit between simulated and observed plasma profiles; simulation of the intestinal luseogliflozin concentration-time profile using the Advanced Compartment Absorption and Transit (ACAT) model in a computer program and estimation of the time spent above a value 10-fold higher than the IC 50 value (TAIC) for SGLT1; and evaluation of the DDI potential of luseogliflozin by considering the percentage of TAIC against the miglitol T max (time for C max ) value (TAIC/T max ). An initial attempt to prove the validity of this method was performed in rats. The resulting TAIC/T max in rats was 32%, suggesting a low DDI potential of luseogliflozin against miglitol absorption. The validity was then confirmed using an in vivo interaction study in rats. In humans, luseogliflozin was expected to have no DDI potential against miglitol absorption, since the TAIC/T max in humans was lower than that in rats. This prediction was proven, as expected, in a clinical interaction study. In conclusion, the present strategy based on a simulation of the intestinal concentration-time profile using dynamic modeling would be useful for assessing the clinical DDI potential of a concomitant agent against drugs absorbed via an intestinal transporter.

Using a Mathematical Modeling To Simulate Pharmacokinetics and Urinary Glucose Excretion of Luseogliflozin and Explore the Role of SGLT1/2 in Renal Glucose Reabsorption

“…A large number of literature studies were investigated to obtain the data for (i) model development: ① physicochemical and biochemical properties of LUS; , ② binding kinetics; ③ affinity to SGLTs for glucose and expression of SGLT data; and ④ physiological parameters for renal tubules . The data have been summarized in Table .…”

“… 19 The data have been summarized in Table 1 . (ii) Model validation: ① PK validation: clinical PK concertation–time profiles 12 , 21 , 23 , 24 and ② UGE validation: clinical cumulative UGE–time and UGE rate–time profiles. 23 , 24 …”

In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor

“…Because even selective SGLT2 inhibitors have an inhibitory effect on SGLT1 and the intestinal concentration of such inhibitors can be much higher than the IC 50 value for SGLT1, we assessed the clinical DDI potential of luseogliflozin against miglitol. Based on the simulated intestinal concentration and the rapid absorption of luseogliflozin, the potential DDI was estimated to be low (Mizuno-Yasuhira et al, 2011). Actually, luseogliflozin reportedly has no clinically relevant effect on the pharmacokinetics of miglitol (Sasaki et al, 2015).…”

Intestinal Absorption and Tissue Distribution of Aza-Sugars from Mulberry Leaves and Evaluation of Their Transport by Sugar Transporters

“…It was reported that miglitol, a synthetic N-hydroxyethyl derivative of DNJ, was absorbed into the bloodstream by a sugar transporter, namely, sodium-glucose cotransporter 1 (SGLT1). 8 Based on this finding, we hypothesized that sugar transporters, such as the sodium-glucose cotransporter (SGLT) or the glucose transporter (GLUT) might facilitate the intestinal absorption and organ uptake of other types of aza-sugars. In the second part of our study, we investigated this in vivo (Experiment 2) and in vitro (Experiment 3) using acknowledged inhibitors of sugar transporters.…”

“…Understanding this information is critical to gain more insight into the action mechanism and safety of aza-sugars once ingested. It was reported that miglitol, a synthetic N -hydroxyethyl derivative of DNJ, was absorbed into the bloodstream by a sugar transporter, namely, sodium-glucose cotransporter 1 (SGLT1) . Based on this finding, we hypothesized that sugar transporters, such as the sodium-glucose cotransporter (SGLT) or the glucose transporter (GLUT) might facilitate the intestinal absorption and organ uptake of other types of aza-sugars.…”