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

Abstract

Aim

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.

Methods

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.

Results

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.

Conclusions

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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Abbreviations

AS:

Allometric scaling

AUC:

Area under the curve

BP:

Blood plasma ratio

BW:

Body weight

CI:

90% confidence interval

CL:

Systemic clearance in central compartment

CL/F:

Clearance after oral administration

CLh:

Hepatic clearance

CLint:

Intrinsic clearance

CLiv:

Clearance after intravenous administration

C max :

Peak concentration

CLr:

Renal clearance

C ss-MRT:

Steady-state concentration- mean residence time

DDI:

Drug–drug interactions

ER:

Excretion ratio

F a :

Absorbed fraction

F :

Bioavailability

FASSIF:

Fasted state simulated intestinal fluid

FESSIF:

Fed state simulated intestinal fluid

FIH:

First in human

F sc :

Scaling factor between observed and predicted data

GK:

Glucokinase

GKA:

Glucokinase activator

H :

Hematocrit

HLM:

Human liver microsomes

IVIVE:

In vitro to in vivo exploration

K a :

Absorption rate constant

K m :

Michelis–Menten constant

MPPGL:

mg protein per liver weight

MRT:

Mean residence time

M.W:

Molecular weight

OATP:

Organic anion transporting polypeptide

Obs:

Observed values

P app :

Apparent permeability coefficient

P eff :

Jejunum effective permeability

P-gp:

P-Glycoprotein

PK:

Pharmacokinetics

PBPK:

Physiologically based pharmacokinetic

rhCYP:

Recombinant human cytochrome P450 enzyme

SAS:

Simple allometric scaling method

Sim:

Simulated values

SGF:

Simulated gastric fluid

SSS:

Single species scaling method

T2DM:

Type 2 diabetic patients

T max :

Time at the peak concentration occurs

V c :

Distribution volume of central compartment

TS:

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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Acknowledgements

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

Funding

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). https://doi.org/10.1007/s40262-018-0631-z

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