Janagliflozin

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 21,880, 24,881, 26,996, and 28,419 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 21,810, 21,840, and 22,845 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.

To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and tolerability of janagliflozin, a novel sodium‐glucose co‐transporter‐2 inhibitor, in Chinese people with type 2 diabetes mellitus (T2DM).

In this study, 36 people with T2DM were randomly assigned in a 1:1:1:1 ratio to receive janagliflozin 25 mg, janagliflozin 50 mg, dapagliflozin 10 mg or placebo. Participants received a single dose on day 1, and were treated once daily from day 4 to day 17.

Following oral administration, janagliflozin was rapidly absorbed, reaching Cmax at 2 hours. The mean half‐life (t1/2) at steady state was approximately 21 to 23 hours. There was no significant accumulation with multiple doses (accumulation factor < 2). In participants treated with janagliflozin 25 mg, janagliflozin 50 mg, dapagliflozin 10 mg or placebo, change in mean 24‐hour urinary glucose excretion from baseline was 92.35, 94.17, 87.61 and 6.26 g after multiple doses, and change in mean fasting plasma glucose level from baseline to day 17 was −2.18, −2.66, −2.79 and 1.70%, respectively. Most adverse events (AEs) were mild or moderate with no deaths, serious AEs, or discontinuations due to AEs.

Single and multiple oral administration (14 days) of janagliflozin 25 mg and 50 mg exhibited favourable PK, PD and tolerability profiles in Chinese people with T2DM, which were comparable to those of dapagliflozin 10 mg. Janagliflozin 25 mg and 50 mg are recommended for further clinical investigation.