Simultaneous Determination of a Novel PD-L1 Inhibitor, IMMH-010, and Its Active Metabolite, YPD-29B, in Rat Biological Matrices by Polarity-Switching Liquid Chromatography-Tandem Mass Spectrometry: Application to ADME Studies

Jianwei Jiang, Xiaowen Zou, Yuke Liu, Xiao Liu, Kai Dong, Xiaoqing Yao, Zhiqiang Feng, Xiaoguang Chen, Li Sheng, Yan Li, Jianwei Jiang, Xiaowen Zou, Yuke Liu, Xiao Liu, Kai Dong, Xiaoqing Yao, Zhiqiang Feng, Xiaoguang Chen, Li Sheng, Yan Li

Abstract

IMMH-010 is a prodrug of YPD-29B, which is a novel PD-L1 inhibitor. A specific and sensitive LC-MS/MS method with polarity switching was developed and validated for the simultaneous determination of IMMH-010 and YPD-29B in rat plasma, liver, brain, urine and fecal samples. Method validation was investigated to demonstrate the lower limit of quantification linearity, precision and accuracy, matrix effect and recovery, stability and dilution reliability for IMMH-010 and YPD-29B. This validated method was successfully applied to investigate the pharmacokinetics, tissue distribution, and excretion of IMMH-010 and YPD-29B in rats. After oral administration of IMMH-010 maleate to rats, IMMH-010 was rapidly and extensively converted to the active metabolite YPD-29B. The areas under the plasma concentration-time curve (AUC) of IMMH-010 and YPD-29B were proportional to the dose in the range of 10-100 mg/kg. IMMH-010 was primarily distributed in the adrenal gland, lymph nodes, heart, liver and spleen. YPD-29B was mainly observed in the liver, lymph, kidney, and lung. Approximately 28.81% of the IMMH-010 dose was recovered in the urine and feces within 72 h, including unchanged IMMH-010 (7.99%) and YPD-29B (20.82%). The results of this study may be useful as a reference for further development of IMMH-010 and PD-L1 inhibitors. Clinical Trial Registration: [https://ichgcp.net/clinical-trials-registry/NCT04343859?term=IMMH-010&draw=2&rank=1], identifier [NCT04343859]."

Keywords: ADME studies.; IMMH-010; LC-MS/MS; PD-L1 inhibitor; YPD-29B; rat biological matrices.

Conflict of interest statement

Authors KD and XY were employed by the company Tianjin chase Sun Pharmaceutical Co. LTD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Jiang, Zou, Liu, Liu, Dong, Yao, Feng, Chen, Sheng and Li.

Figures

FIGURE 1
FIGURE 1
Structure and product ion spectra with proposed MS fragmentations: parent ion (A) and daughter ion (B) of IMMH-010 and parent ion (C) and daughter ion (D) of YPD-29B.
FIGURE 2
FIGURE 2
Typical MRM chromatograms of IMMH-010, IS1, YPD-29B and IS2 in plasma, liver, brain and urine and feces obtained from blank sample and LLOQ samples.
FIGURE 3
FIGURE 3
Concentration-time profiles of IMMH-010 and its active metabolites YPD-29B in rats after a single i. g. administration of IMMH-010 maleate at doses of 10, 30, 100 mg/kg (n = 5).
FIGURE 4
FIGURE 4
Does proportionality of Cmax (left) and AUC0-t (right) for IMMH-010 and YPD-29B in plasma with a single i. g. administration of IMMH-010 maleate at doses of 10, 30, 100 mg/kg.
FIGURE 5
FIGURE 5
Tissue distribution of IMMH-010 and YPD-29 B in rats after a single i. g. administration of IMMH-010 maleate at 10 mg/kg (n = 5).

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Source: PubMed

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