Pharmacokinetics, Bioavailability, and Tissue Distribution of the Kirsten Rat Sarcoma Inhibitor Adagrasib in Rats Using UPLC-MS/MS

Abstract

Purpose

Adagrasib is a selective and reversible inhibitor of KRAS G12C, which significantly delays the progression of solid tumors. However, the absorption, distribution, metabolism, and excretion of adagrasib in vivo are unclear. This study explores the absorption and distribution of adagrasib in vivo.

Methods

An ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method was established for the determination of adagrasib in the rat plasma and tissue. Sprague-Dawley rats were intravenous administrated (5 mg/kg) and oral administrated (30 mg/kg) with adagrasib, and the plasma concentration of adagrasib was determined. After single oral administration of adagrasib (30 mg/kg), the heart, liver, spleen, lung, kidney, intestine, and pancreas were excised. The organs were homogenized with saline solution, and the concentration of adagrasib in tissues was determined.

Results

The intra- and inter-day accuracy were from 84.90% to 113.47%, and the precision was within ±15%. The matrix effect and recovery were within ±15%. The maximum plasma concentration (C_max) of adagrasib was 677.45 ± 58.72 ng/mL. The elimination half-life time (t_1/2) was 3.50 ± 0.21 h after oral administration and 2.08 ± 0.54 h after intravenous administration. The oral bioavailability was 50.72%. The highest concentrations of adagrasib in liver was 5047.80 ± 676.48 ng/g at 2 h after administration, and it was still detectable at 24 hours after administration.

Conclusion

Adagrasib was slowly absorbed and cleared rapidly, and it was also widely distributed in vivo. This study provides a potential reference for adagrasib in clinical studies.

Keywords:

• adagrasib
• UPLC-MS/MS
• pharmacokinetics
• tissue distribution

Abbreviations

AUC, area under the plasma concentration–time curve; C_max, maximum drug concentration; IS, internal standard; LLOQ, lower limit of quantification; QC, quality control; RAS, rat sarcoma; UPLC-MS, ultra performance liquid chromatography-tandem mass spectrometer; t_1/2, half-life elimination time; T_max, time to C_max; AUC0-t, area under the concentration–time curve from 0 to the last time point; MRT, mean residence time; CL, clearance rate; V_d, apparent volume of distribution.

Disclosure

The authors declare that there are no conflicts of interest.

Additional information

Funding

This work was supported by Hubei Province’s Outstanding Medical Academic Leader Program (Yijun Tang), China International Medical Foundation (202334).