Development and validation of a LC-MS/MS method for simultaneous determination of TQ-A3326 and its major metabolites in human plasma, urine and feces: application to pharmacokinetic assay

Abstract

1. TQ-A3326 has been developed as a new drug by modifying the structure of daclatasvir with deuterium. The pharmacokinetics (PK) of TQ-A3326 in human remains unclear. The aim of the present study was to establish a LC-MS/MS method to investigate preliminarily the PK characteristics of TQ-A3326 and its major metabolites in healthy Chinese volunteers. All volunteers were administrated TQ-A3326 (60 mg). Plasma, feces and urine samples were extracted through protein precipitation. A rapid and sensitive LC-MS/MS method was successfully developed and applied to assess the PK properties of TQ-A3326.

2. The AUC_0-t and C_max were 39516.3 ± 10778.5, 1034.6 ± 452.9 and 71.0 ± 49.5 ng·h·mL⁻¹, and 1411.2 ± 325.4, 52.9 ± 16.4 and 1.8 ± 0.5 ng·mL⁻¹, respectively, for TQ-A3326, M2-D and M4-D. Feces were the predominant route of elimination of TQ-A3326. M2-D was an abundant metabolite in feces and urine, representing 23.72% and 0.24% of the dose, respectively.

3. The measurements of TQ-A3326 and its active metabolites would help to better understand the predominant route of elimination of the prototype drug, and provide meaningful information for further investigation of the bioactive mechanism of TQ-A3326 and its clinical applications.

Keywords:

• TQ-A3326
• HPLC-MS/MS
• NS5A inhibitor
• pharmacokinetics
• excretion

Ethical approval

Experimental protocols and procedures were approved by the Ethics Committee of the Third Hospital of Changsha, China, following the Clinical Trial Authorization of the CFDA (Approval No. 2017L04988).

Disclosure statement

The authors report no conflict of interest.

Data availability statement

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This project was funded by the Ministry of Science and Technology of China under the National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development [No.2017ZX09201006010] and the Changsha Science and Technology Plan Project for “Changsha Anti-Infective Drugs Engineering Technology Research Center” [No. kq1801120]. The funding bodies had no role in the design of the study, the collection, analysis, or interpretation of the data, or writing the manuscript.