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Background: Janagliflozin is a novel sodium–glucose cotransport-2 inhibitor. Despite its remarkable effect in glycemic control, no systematic research has evaluated the effect of renal impairment (RI) on its pharmacokinetics and pharmacodynamics. Methods: Here, patients with T2DM (n = 30) were divided into normal renal function (eGFR ≥ 90 mL/min/1.73 m2), mild RI (eGFR between 60 and 89 mL/min/1.73 m2), moderate RI-I (eGFR between 45 and 59 mL/min/1.73 m2), and moderate RI-II (eGFR between 30 and 44 mL/min/1.73 m2) groups. They were administered 50 mg janagliflozin orally, and plasma and urine samples were collected for the determination of janagliflozin concentration. Results: Following oral administration, janagliflozin was rapidly absorbed, with the time to Cmax of 2–6 h for janagliflozin and 3–6 h for its metabolite XZP-5185. Plasma exposure levels were similar for janagliflozin in T2DM patients with or without RI but decreased for the metabolite XZP-5185 in T2DM patients with eGFR between 45 and 89 mL/min/1.73 m2. Janagliflozin significantly promoted the excretion of urinary glucose, even in patients with reduced eGFR. Janagliflozin was well tolerated in patients with T2DM with or without RI, and no serious adverse events (SAEs) occurred during this trial. Conclusions: The exposure levels of janagliflozin in T2DM patients were slightly increased with worsening of RI (i.e., 11% increase in the AUC in patients with moderate RI compared with the normal renal function group). Despite worsening of renal function, janagliflozin exerted a significant pharmacologic effect and was well tolerated, even in patients with moderate RI, implying a promising role in the treatment of patients with in T2DM. Registration: China Drug Trial register (http://www.chinadrugtrials.org.cn/I) identifier no.: CTR20192721. [ABSTRACT FROM AUTHOR]

Aim: To apply model-informed drug development (MIDD) approach to support the decision making in drug development and accelerate the clinical development of janagliflozin, an orally selective SGLT2 inhibitor. Method: We previously developed a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model of janagliflozin based on preclinical data to optimize dose design in the first-in-human (FIH) study. In the current study, we used clinical PK/PD data of the FIH study to validate the model and then simulate the PK/PD profiles of multiple ascending dosing (MAD) study in healthy subjects. Besides, we developed a population PK/PD model of janagliflozin to predict steady-state urinary glucose excretion (UGE [UGE,ss]) in healthy subjects in the Phase 1 stage. This model was subsequently used to simulate the UGE, ss in patients with type 2 diabetes mellitus (T2DM) based on a unified PD target (ΔUGEc) across healthy subjects and patients with T2DM. This unified PD target was estimated from our previous work of model-based meta-analysis (MBMA) for the same class of drugs. The model-simulated UGE,ss in patients with T2DM was validated by data from the clinical Phase 1e study. Finally, at the end of the Phase 1 study, we simulated the 24-week hemoglobin A1c (HbA1c) level in patients with T2DM of janagliflozin based on the quantitative UGE/FPG/HbA1c relationship informed by our previous MBMA study for the same class of drugs. Results: The pharmacologically active dose (PAD) levels of multiple ascending dosing (MAD) study were estimated to be 25, 50,100 mg once daily (QD) for 14 days based on the effective PD target of approximately 50 g daily UGE in healthy subjects. Besides, our previous MBMA analysis for the same class of drugs has provided a unified effective PD target of ΔUGEc approximately 0.5–0.6 g/(mg/dL) in both healthy subjects and patients with T2DM. In this study, the model-simulated steady-state ΔUGEc (ΔUGEc,ss) of janagliflozin in patients with T2DM were 0.52, 0.61 and 0.66 g/(mg/dL) for 25, 50, 100 mg QD dose levels. Finally, we estimated that HbA1c at 24 weeks would decrease 0.78 and 0.93 from baseline for the 25 and 50 mg QD dose groups. Conclusions: The application of MIDD strategy adequately supported the decision making at each stage of janagliflozin development process. A waiver of Phase 2 study was successfully approved for janagliflozin based on these model-informed results and suggestions. This MIDD strategy of janagliflozin could be further utilized to support the clinical development of other SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

A series of mesoporous alumina (MA) doped with acidic (Ti, W) or alkaline earth (Ba, Mg) elements were prepared. They were used as the supports for Pd catalysts. These catalysts were characterized by N2 sorption, X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, infrared spectroscopy of CO adsorption and temperature-programmed reduction. Complete oxidation of toluene on these catalysts was tested in a fixed-bed micro-reactor. The results of in situ IR of CO adsorption indicated that the doping of basic element was beneficial for the dispersion of PdO particles, while the doping of acid element suppressed the dispersion of PdO particles. The binding energy of Pd in Pd/Ba-MA shifted to high energy, indicating that the interaction between PdO and support was enhanced. The results of H2-TPR showed that the reducibility of PdO doped with alkaline element was stronger than those of catalysts doped with acidic element. The doping of basic elements promoted the dispersion of PdO particles, changed the electronic state of Pd and enhanced the reducibility of PdO, which led to its high activity. The catalysts doped with the basic elements had higher activities than those doped with acidic elements, among which the Pd/Ba-MA catalyst had the highest activity among all catalysts. [ABSTRACT FROM AUTHOR]

To investigate the significance of waist circumference (WC), body mass index (BMI) and hyperinsulinaemia A (HIns) in evaluating metabolic syndrome (MS). Clinical data from middle-aged and senile individuals (middle-senile group) who received glucose tolerance test after diabetes mellitus screening and a group of subjects who received annual oral glucose tolerance test (OGTT) for diabetes mellitus screening (adult group) were collected. Data were collected by use of special messengers, input into a computer data base and analyzed using SAS 5.0 software by expert staff. Abnormal WC and BMI were determined according to International Diabetes Federation (IDF) and Chinese Diabetes Society (CDS) criteria. HIns was ascertained if fasting insulin (FIns) ⩾ 15 mU/L, and/or 2-hour insulin after a glucose challenge was (2hPIns) ⩾ 80 mU/L. Abnormalities in WC, BMI and HIns were all found to be risk factors for abnormal glucose metabolism, hypertension and dyslipidemia. In the middle-senile group, the abnormality rate of WC and HIns as well as the overall insulin level were significantly higher than those in the adult group. The abnormality rate of BMI was higher in the adult group, and HIns was mostly seen in impaired glucose test (IGT) and normal glucose test (NGT). The concordance rate of WC and BMI diagnostic criteria for evaluating obesity in the middle-senile and adult groups were 77.5% and 74.3%, respectively. When only the WC criterion was used for evaluating the existence of insulin resistance, there was a 28.2%missed diagnosis rate for MS patients. WC, BMI and HIns were all risk factors for abnormal glucose metabolism, hypertension and dyslipidemia. There was differing prevalence in the different populations. The combination of WC, BMI and HIns might be more helpful in identifying MS at early stage. [ABSTRACT FROM AUTHOR]