Development of a Physiologically Based Pharmacokinetic Model for Sinogliatin, a First-in-Class Glucokinase Activator, by Integrating Allometric Scaling, In Vitro to In Vivo Exploration and Steady-State Concentration–Mean Residence Time Methods: Mechanistic Understanding of its Pharmacokinetics



The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration–mean residence time (Css-MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans.


Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and Css-MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms. On this basis, an initial mechanistic PBPK model of sinogliatin was developed. The initial PBPK model was verified using observed data from a single ascending dose (SAD) study and further optimized with various strategies. The final model was validated by simulating sinogliatin pharmacokinetics under a fed condition. The validated model was applied to support a clinical drug–drug interaction (DDI) study design and to evaluate the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure.


The two-species scaling method using rat and dog data (TS-rat,dog) was the best AS method in predicting human systemic clearance in the central compartment (CL). The IVIVE method confirmed that sinogliatin was predominantly metabolized by cytochrome P450 (CYP) 3A4. The Css-MRT method suggested dog pharmacokinetic profiles were more similar to human pharmacokinetic profiles. The estimated CL using the AS and IVIVE approaches was within 1.5-fold of that observed. The Css-MRT method in dogs also provided acceptable prediction of human pharmacokinetic characteristics. For the PBPK approach, the 90% confidence intervals (CIs) of the simulated maximum concentration (Cmax), CL, and area under the plasma concentration–time curve (AUC) of sinogliatin were within those observed and the 90% CI of simulated time to Cmax (tmax) was closed to that observed for a dose range of 5–50 mg in the SAD study. The final PBPK model was validated by simulating sinogliatin pharmacokinetics with food. The 90% CIs of the simulated Cmax, CL, and AUC values for sinogliatin were within those observed and the 90% CI of the simulated tmax was partially within that observed for the dose range of 25–200 mg in the multiple ascending dose (MAD) study. This PBPK model selected a final clinical DDI study design with itraconazole from four potential designs and also evaluated the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure.


Sinogliatin pharmacokinetic properties were mechanistically understood by integrating all four methods and a mechanistic PBPK model was successfully developed and validated using clinical data. This PBPK model was applied to support the development of sinogliatin.

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Allometric scaling


Area under the curve


Blood plasma ratio


Body weight


90% confidence interval


Systemic clearance in central compartment


Clearance after oral administration


Hepatic clearance


Intrinsic clearance


Clearance after intravenous administration

C max :

Peak concentration


Renal clearance

C ss-MRT:

Steady-state concentration- mean residence time


Drug–drug interactions


Excretion ratio

F a :

Absorbed fraction

F :



Fasted state simulated intestinal fluid


Fed state simulated intestinal fluid


First in human

F sc :

Scaling factor between observed and predicted data




Glucokinase activator

H :



Human liver microsomes


In vitro to in vivo exploration

K a :

Absorption rate constant

K m :

Michelis–Menten constant


mg protein per liver weight


Mean residence time


Molecular weight


Organic anion transporting polypeptide


Observed values

P app :

Apparent permeability coefficient

P eff :

Jejunum effective permeability






Physiologically based pharmacokinetic


Recombinant human cytochrome P450 enzyme


Simple allometric scaling method


Simulated values


Simulated gastric fluid


Single species scaling method


Type 2 diabetic patients

T max :

Time at the peak concentration occurs

V c :

Distribution volume of central compartment


Two species scaling method

V d :

Distribution volume of peripheral compartment

V max :

Enzyme maximum rate of metabolite formation

V ss :

Steady-state distribution volume


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We acknowledge Dr Bo Liu for his comments for the SimCYP® software technology support.


This study was supported by the National Natural Science Foundation of China (Nos. 81403013 and 81403015) and the ‘13th Five-Year’ National Major New Drug Projects (Nos. 2017ZX09101001-002-001 and 2017ZX09304031-001).

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Correspondence to Dongyang Liu or Xijing Chen or Pei Hu.

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Conflict of interest

Yi Zhang, Shuang Ren, and Li Chen are employees of Hua Medicine (Shanghai) Ltd., the company developing sinogliatin. Ling Song, Ji Jiang, Dongyang Liu, Xijing Chen, and Pei Hu declare no conflicts of interest relevant to the contents of this manuscript.

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Song, L., Zhang, Y., Jiang, J. et al. Development of a Physiologically Based Pharmacokinetic Model for Sinogliatin, a First-in-Class Glucokinase Activator, by Integrating Allometric Scaling, In Vitro to In Vivo Exploration and Steady-State Concentration–Mean Residence Time Methods: Mechanistic Understanding of its Pharmacokinetics. Clin Pharmacokinet 57, 1307–1323 (2018).

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