Mechanistic Modeling of Empagliflozin: Predicting Pharmacokinetics, Urinary Glucose Excretion, and Investigating Compensatory Role of SGLT1 in Renal Glucose Reabsorption

J Clin Pharmacol. 2024 Feb 16. doi: 10.1002/jcph.2413. Online ahead of print.ABSTRACTThe aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate i...
Source: The Journal of Clinical Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research