Shandong Xuanzhu Pharmaceutical Technology Co., Ltd.

Janagliflozin is an orally selective SGLT2 inhibitor. To predict human pharmacokinetics/pharmacodynamics (PK/PD) characteristics of janagliflozin. To design optimal starting dose and effective dose for janagliflozin first-in-human (FIH) study.

Animal PK/PD properties of janagliflozin were obtained from preclinical in vivo and in vitro study. Pharmacologically effective level of same class SGLT2 inhibitors were assessed through preclinical and clinical efficacy data of dapagliflozin, empagliflozin and canagliflozin. Human PK parameters and profiles of janagliflozin were predicted by various methods such as allometric scaling (AS), dedrick and PK/PD modeling analysis. Mechanistic PK/PD model was developed to describe janagliflozin-mediated impact on urinary glucose excretion (UGE). Human IC₅₀ was scaled from rat model-estimated IC₅₀ by correcting interspecies difference of in vitro IC₅₀ and plasma f_u of rat and human. The quantitative PK/PD prediction of janagliflozin was evaluated via observed PK/PD profiles of healthy subjects. Predicted PK/PD characteristics of janagliflozin were applied in FIH dose design. Optimal starting dose was suggested by considering preclinical PD and toxicity data of janagliflozin. Effective dose was suggested by considering pharmacologically effective level of same class drugs.

PK/PD characteristics of janagliflozin in preclinical species were summarized. Pharmacologically effective level for SGLT2 inhibitors was defined as 25~30% ΔUGE (ΔUGE=--(PG*GFR)_within24h) based on efficacy data of three same class drugs. Human predicted CL, V_ss and F were 1.04 L/h, 77.5 L and 0.80. Predicted AUC and C_max of janagliflozin of 10 and 50 mg were within 0.47~2.08 fold of observed values. Predicted human UGE_0-24 h and UGE_0-144 h of 10 and 50 mg dose range were within 0.66~1.41 fold of observed values. Optimal starting dose and pharmacologically active dose (PAD) were suggested as 10 mg and 50 mg. Dose range for FIH study was designed as 10-450 mg.

This study predicted human PK/PD characteristics of janagliflozin based on preclinical data and provide optimal dose design for janagliflozin FIH study based on pharmacologically effective level of same class drugs.

Benapenem is a novel carbapenem. The objective of this study was to determine the pharmacokinetic (PK)/pharmacodynamic (PD) cutoff values and evaluate the optimal administration regimens of benapenem for the treatment of bacterial infections via PK/PD modeling and simulation. Ertapenem was used as a control. Infected mice received an intravenous (i.v.) injection of benapenem or ertapenem of 14.6, 58.4, or 233.6 mg/kg of body weight, and the PK/PD profiles were evaluated.

Aim: Janagliflozin is a novel, orally selective sodium-glucose co-transporter-2 (SGLT2) inhibitor, which showed good efficacy and safety in preclinical study. The objective of this study is to develop and validate the HPLC–MS/MS method to determine janagliflozin in both of human urine and plasma. Methods: Janagliflozin was separated on Waters Xbridge Phenyl C18 column and detected on API 4000 tandem mass spectrometer with ESI source in negative mode. Results: This method provided good linearity in the range of 5–5000 ng/ml and 5–1000 ng/ml in plasma and urine. The matrix effect and extraction recoveries across three concentration levels were consistent. Conclusion: This validated method is reliable and has been successfully applied to a first-in-human trial of janagliflozin in Chinese subjects.