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A Model-Informed Approach to Accelerate the Clinical Development of Janagliflozin, an Innovative SGLT2 Inhibitor

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Abstract

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.

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Author information

Author notes

  1. Ling Song, Xiaoxu Wang have equally contributed to this study.

Authors and Affiliations

  1. Drug Clinical Trial Center, Peking University Third Hospital, Beijing, 100191, China

    Ling Song, Xiaoxu Wang, Haiyan Li & Dongyang Liu

  2. Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China

    Ling Song & Xiaoxu Wang

  3. Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China

    Ling Song, Haiyan Li & Dongyang Liu

  4. Huisheng Bio-pharmaceutical Co., Ltd, Jilin, 135099, China

    Jingfang Sun & Xinyu Hu

  5. Clinical Pharmacology Research Center, Peking Union Medical College Hospital & Chinese Academy of Medical Sciences, Beijing, 100032, China

    Pei Hu & Dongyang Liu

Authors
  1. Ling Song
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Corresponding authors

Correspondence to Pei Hu or Dongyang Liu.

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Funding

The study was supported by the National Natural Science Foundation of China (No. 81903717), The Bill & Melinda Gates Foundation, Grant/Award Number: INV-007625, and The Peking University Third Hospital Clinical Project, Grant/Award Number: BYSYFY2021006.

Conflict of Interest

Jingfang Sun and Xinyu Hu are employees in Huisheng Bio-pharmaceutical (Jilin) Ltd., the company owing janagliflozin. Ling Song, Xiaoxu Wang, Haiyan Li, Pei Hu and Dongyang Liu, declare no conflicts of interest that might be relevant to the contents of this manuscript.

Ethical Approval

The data used in this study were collected in line with the principles of the Declaration of Helsinki. Approval was granted by institutional review boards and independent ethics committees for each study from which data were used in this work.

Data Availability

All data generated or analysed during this study are included in this published article (and its supplementary information files).

Authors’ contributions

Dr. Ling Song, Dongyang Liu and Pei Hu designed the study, Dr. Ling Song, Xiaoxu Wang conducted the modeling and simulation work. Dr. Jingfang Sun and Xinyu Hu offered the preclinical and clinical raw data. Dr.Haiyan Li gave the writing suggestion for this article.

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Supplementary file1 (PDF 702 kb)

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Song, L., Wang, X., Sun, J. et al. A Model-Informed Approach to Accelerate the Clinical Development of Janagliflozin, an Innovative SGLT2 Inhibitor. Clin Pharmacokinet 62, 505–518 (2023). https://doi.org/10.1007/s40262-022-01209-z

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