Assessment of Remogliflozin Etabonate, a Sodium-Dependent Glucose Co-Transporter-2 Inhibitor, as a Perpetrator of Clinical Drug Interactions: A Study on Drug Transporters and Metabolic Enzymes

Abstract

Type 2 diabetes mellitus is a chronic disease characterized by progressive deterioration of glycemic control and an increased risk of associated complications. Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose transporter-2 inhibitor that was under development to treat type 2 diabetes. This work investigated the in vitro inhibition of efflux and uptake transporters and cytochrome P450 enzymes by remogliflozin etabonate, remogliflozin and a number of other metabolites. As well, the ability of remogliflozin to induce cytochrome P450 enzymes in human hepatocytes was examined. Remogliflozin etabonate, remogliflozin and GSK279782 (an active pharmacological metabolite of remogliflozin) were inhibitors of organic anion transporting polypeptide-1B1 with IC 50 values of 5.3, 25 and 14 µM, respectively. Remogliflozin etabonate and remogliflozin were inhibitors of organic cation transporter-1 with IC 50 values of 43 and 39 µM, respectively. In contrast, remogliflozin etabonate, remogliflozin, GSK279782, and GSK333081 (a metabolite of remogliflozin) were not inhibitors of P-glycoprotein, a number of other renal transporters, or cytochrome P450 enzymes. Further, three circulating glucuronide metabolites found in human plasma were not inhibitors of cytochrome P450 enzymes or organic anion transporters. Remogliflozin etabonate, but not remogliflozin or GSK279782, activated the pregnane X Receptor in vitro. Further studies demonstrated that remogliflozin (up to 100 µM) did not induce cytochrome P450 3A4 or 1A1 mRNA in human hepatocytes; however a small increase was noted for CYP2B6 mRNA. Combined with pharmacokinetic data from healthy volunteers and diabetic subjects, these in vitro investigations provide a low drug interaction potential for remogliflozin etabonate, remogliflozin and the associated metabolites to be perpetrators of clinical drug interactions. This information has been used to guide the design of clinical studies with remogliflozin etabonate when given with other co-medications.

Safety, pharmacokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitus

“…In this study, no effect of remogliflozin etabonate on metformin PK parameters was observed. The findings from this study are consistent with the reported lack of inhibition by remogliflozin etabonate, remogliflozin, and GSK279782 on a panel of metabolic enzymes and transporters, including organic cation transporters involved with metformin renal secretion [39]. …”

Effect of canagliflozin on the pharmacokinetics of glyburide, metformin, and simvastatin in healthy participants

“…No dose adjustment is required when metformin is coadministered with canagliflozin. The measured metformin concentrations in the current study are comparable to historical steady state values of metformin in published studies …”

“…The measured metformin concentrations in the current study are comparable to historical steady state values of metformin in published studies. 21,22 In Study 3, the dose selected is within the recommended dose range for simvastatin. Coadministration of canagliflozin increased the C max of simvastatin (CYP3A4 substrate) by 9% and AUC by 12% while C max of simvastatin acid increased by 26% and AUC by 18%.…”

Assessment of the Drug Interaction Risk for Remogliflozin Etabonate, a Sodium-Dependent Glucose Cotransporter-2 Inhibitor: Evidence from In Vitro, Human Mass Balance, and Ketoconazole Interaction Studies

“…This observation provides strong clinical evidence that efflux transporters such as Pgp and breast cancer resistance protein do not limit the intestinal absorption of remogliflozin etabonate, remogliflozin, or metabolites; this is consistent with remogliflozin etabonate being a Biopharmaceutics Drug Disposition Classification System class 1 drug displaying high permeability and solubility (GSK data on file; Benet et al, 2011) and with remogliflozin being a Biopharmaceutics Drug Disposition Classification System class III compound having low permeability and high solubility. However, remogliflozin has demonstrated low central nervous system penetration in the rat, which may be related to Pgp efflux at the blood-brain barrier, its low passive permeability, or other mechanisms (Polli et al, 2012). This is not a concern in humans, because the potential for drug interactions with Pgp inhibitors at the blood-brain barrier is very small (Eyal et al, 2009).…”