Available online 23 September 2022, 106298

Physiologically based pharmacokinetic models of janagliflozin were developed

Models were used to predict drug exposure changes in diabetic populations

Janagliflozin exposure was increased in T2DM populations with elevated cirrhosis severity

Risk benefit assessment is recommended for T2DM patients with cirrhosis

Models predicted stable pharmacokinetic profiles in T2DM populations with renal impairment

Janagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes mellitus (T2DM). The janagliflozin pharmacokinetics (PK) in T2DM patients with cirrhosis or renal impairment (RI) are unknown. To predict the janagliflozin PK in these patients, we constructed a physiologically based PK (PBPK) model that predicted the janagliflozin PK in normal animals. The model was extrapolated to healthy humans and optimized with the measured data. A PBPK model for T2DM patients was developed and optimized with the measured data. Based on the physiological alterations in cirrhosis or RI patients, the T2DM model was applied to predict the janagliflozin PK in these patients. Results were validated using fold error values. The predicted AUC values were 21880, 24881, 26996, and 28419 ng/ml·h in T2DM patients with no cirrhosis, Child-Pugh-A, B, and C, respectively, and those in T2DM patients with RI-mild, RI-moderate, and RI-severe were 21810, 21840, and 22845 ng/ml·h, respectively. Janagliflozin exposure increased with increasing cirrhosis severity, whereas it remained stable regardless of the RI severity. The PBPK model predicted the janagliflozin PK in patients with T2DM and liver cirrhosis or RI. Dose adjustment is less critical for these patients. Risk benefit assessment in janagliflozin dosing for T2DM patients with liver disease is recommended.

janagliflozin

T2DM

liver cirrhosis

renal impairment

PBPK model

© 2022 The Authors. Published by Elsevier B.V.