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Background: PB-201, a partial, pancreas/liver-dual glucokinase activator, showed good tolerance and glycaemic effects in multinational studies. We aimed to determine its optimal dose and to evaluate its safety, pharmacokinetics, and pharmacodynamics in Chinese patients with type 2 diabetes. Methods: In this double-blind, randomised, four-period, crossover, phase 1 trial in China (NCT03973515), adult patients with drug-naive type 2 diabetes were randomised (1:1:1:1) to four sequence groups using a computer-generated randomisation table. In each period, they received oral placebo or PB-201 (50+50, 100+50, or 100+100 mg split doses) for 7 days. Investigators and patients were masked to treatment assignment. The primary endpoints were safety and pharmacokinetics. Continuous glucose monitoring was used to delineate the glucose excursion profile. Findings: Between July 18, 2019 and September 05, 2019, 16 patients were randomised. PB-201 showed a dose-proportional pharmacokinetic profile and dose-dependent lowering of blood glucose, similar to findings in non-Chinese populations. PB-201 at 100+50 and 100+100 mg increased mean time in range (49·210% [standard deviation 27], 56·130% [25], and 63·330% [20] with three doses, respectively) versus placebo (49·380% [27]) and reduced estimated glycated haemoglobin from baseline (−0·5445% [1·654], −1·063% [1·236], and −1·888% [1·381] vs −0·581% [1·200]). All treatment-emergent adverse events were mild. No patients had hypoglycaemia with venous/capillary glucose

A specific and sensitive method was firstly developed using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC–MS/MS) to simultaneously quantify TPN729 and its metabolites (TPN729-D1, TPN729-D2, TPN729M15-3 and TPN729M3) in human plasma and (TPN729-D1, TPN729-D2, TPN729M15-3 and TPN729M14) in human urine. Protein precipitation and direct dilution were used to extract TPN729 and its metabolites from plasma and urine, respectively. Ionization of TPN729, TPN729-D1, TPN729-D2, TPN729M15-3, TPN729M3, TPN729M14 and sildenafil (internal standard, IS) was performed using an electrospray ionization (ESI) source in positive mode and detection was carried out with multiple reaction monitoring (MRM) mode. This assay method for TPN729 and its five metabolites has been fully validated in terms of sensitivity, linearity, lower limit of quantification (LLOQ), precision, accuracy, stability, matrix effect and recovery. The LLOQ of TPN729/TPN729-D1/TPN729-D2/TPN729M15-3/TPN729M3 in human plasma and TPN729/TPN729-D1/TPN729-D2/TPN729M15-3/TPN729M14 in human urine were 0.200/0.500/2.00/0.500/1.00 ng/mL and 4.00/2.50/10.0/2.50/1.00 ng/mL, respectively. Inter- and intra-batch precision of TPN729 and its metabolites were less than 15% and the accuracy was within ±15% for both plasma and urine. The extraction recoveries of all analytes at three concentration levels were consistent. In conclusion, the validation results showed that this method was robust, specific, and sensitive and it can successfully fulfill the requirement of clinical pharmacokinetic study of TPN729 in Chinese healthy subjects.

Purpose To accelerate early phase clinical development of a novel drug, teriflunomide sodium, to treat systemic lupus erythematosus (SLE) based on the data of leflunomide. Methods Based on a pharmacokinetic (PK) study assessing the relative bioavailability of teriflunomide sodium compared to leflunomide, a population pharmacokinetic (Pop PK) analysis was firstly conducted using non-linear mixed effect model. Covariates were thoughtfully screened after Pop PK model evaluation and qualification using various diagnostic plots, visual predicted check (VPC) and bootstrap method. In order to predict teriflunomide PK profiles for multiple dosing of teriflunomide sodium in SLE patients, a model integrating enterohepatic circulation (EHC) mechanism was utilized to simulate the teriflunomide PK profile after multiple dosing of 20 mg/day leflunomide, and compare it to the teriflunomide PK profile in a 20 mg/day leflunomide multiple dose study in rheumatoid arthritis patients. Validated EHC PK model was applied to optimize dose regimen for teriflunomide sodium in SLE patients. Results A population one-compartment model with pulsed EHC characteristic was developed to capture teriflunomide PK profiles after administration of leflunomide and teriflunomide sodium. Body weight and male sex were found to significantly increase apparent volume of central compartment. ABCG2 34G>A polymorphism was found to significantly change apparent clearance and absorption rate. The Pop PK model was evaluated and validated. After this model was confirmed to capture EHC characteristics of teriflunomide in both healthy subjects and patients with rheumatoid arthritis after single and multiple dosing leflunomide, it was applied to suggest dose regimen of teriflunomide sodium in phase II study. Conclusions The pulsed EHC Pop PK model characterized the teriflunomide PK processes well in both healthy subjects and patients. Body weight, sex, and ABCG2 34G>A genotype were identified to significantly affect PK characteristics. The developed EHC Pop PK model exhibited the ability to predict PK profiles of teriflunomide in patients after long-term dosing and could be utilized to support phase II trial design.