Development and validation of a robust and sensitive HPLC-MS/MS method for the quantitation of MRTX849 in plasma and its application in pharmacokinetics

Du, Ping; Xuan, Lingling; An, Zhuoling; Zhang, Yuhui

doi:10.1039/d1an01928g

Cited by 5 publications

(3 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, this method was developed for analyzing a small volume sample (10 μl), enhancing the suitability of the developed method to measure hundreds of low-volume samples from preclinical studies that are often performed in small rodents with a limitation of the blood volume. Our developed method provided merit over the previously published analytical method for adagrasib in rat plasma (Du et al, 2022) because the previous study only refers to plasma analysis while in this new assay we incorporated seven mouse tissue-related matrices in addition to mouse plasma.…”

Section: Resultsmentioning

confidence: 99%

“…To obtain such knowledge, a reliable quantification method to determine the adagrasib concentration in biological samples is essential. To our knowledge, only one recent publication describes a validated method to quantify adagrasib in a single biological matrix, that is, rat plasma (Du et al, 2022). The mentioned method utilized protein precipitation (PP) with methanol to treat 50 μl of rat plasma in a vial format.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development and validation of an HPLC–MS/MS method to quantify the KRAS inhibitor adagrasib in mouse plasma and tissue‐related matrices

Retmana,

Loos,

Schinkel

et al. 2023

Biomedical Chromatography

View full text Add to dashboard Cite

We developed and validated an assay utilizing a liquid chromatography–tandem mass spectrometry technique to quantify the KRAS inhibitor adagrasib in mouse plasma and seven tissue‐related matrices. The straightforward protein precipitation technique was selected to extract adagrasib and the internal standard salinomycin from the matrices. Gradient elution of acetonitrile and water modified with 0.5% (v/v) ammonium hydroxide and 0.02% (v/v) acetic acid on a C18 column at a flow rate of 0.6 ml/min was applied to separate the analytes. Both adagrasib and salinomycin were detected with a triple quadrupole mass spectrometer with positive electrospray ionization in a selected reaction monitoring mode. A linear calibration range of 2–2,000 ng/ml of adagrasib was demonstrated during the validation. In addition, the reported precision values (intra‐ and inter‐day) were between 3.5 and 14.9%, while the accuracy values were 85.5–111.0% for all tested levels in all investigated matrices. Adagrasib in mouse plasma was reported to have good stability at room temperature, while adagrasib in tissue‐related matrices was stable on ice for up to 4 h (matrix dependent). Finally, this method was successfully applied to determine the pharmacokinetic profile and tissue distribution of adagrasib in wild‐type mice.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development and validation of an HPLC–MS/MS method to quantify the KRAS inhibitor adagrasib in mouse plasma and tissue‐related matrices

Retmana,

Loos,

Schinkel

et al. 2023

Biomedical Chromatography

View full text Add to dashboard Cite

show abstract

“…The t 1/2 was 10.13 h, the time to reach the maximum plasma concentration (t max ) was 6 h, and the maximum concentration (C max ) was 122.3 ng/mL after oral administration (15 mg/kg). 14 Fell evaluated the intravenous and oral pharmacokinetic parameters of adagrasib in mice, rats, and dogs. 15 The t 1/2 after intravenous administration (3 mg/kg) was 1.51 h (mouse), 2.57 h (rat), and 7.56 h (dog).…”

Section: Introductionmentioning

confidence: 99%

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

Lei,

Shen,

Tang

et al. 2024

DDDT

View full text Add to dashboard Cite

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.

show abstract

Development and validation of an ultra‐performance liquid chromatography–tandem mass spectrometry method to quantify the small molecule inhibitors adagrasib, alectinib, brigatinib, capmatinib, crizotinib, lorlatinib, selpercatinib, and sotorasib in human plasma

Hollander,

Zimmerman,

Piet

et al. 2024

Biomedical Chromatography

View full text Add to dashboard Cite

Small molecule inhibitors (SMIs) are increasingly being used in the treatment of non‐small cell lung cancer. To support pharmacokinetic research and clinical treatment monitoring, our aim was to develop and validate an ultra‐performance liquid chromatography–mass spectrometry (UPLC‐MS/MS) assay for quantification of eight SMIs: adagrasib, alectinib, brigatinib, capmatinib, crizotinib, lorlatinib, selpercatinib, and sotorasib. Development of the UPLC‐MS/MS assay was done by trying different columns and eluents to optimize peak shape. The assay was validated based on guidelines of the European Medicines Agency. Chromatographic separation was performed with a gradient elution using ammonium formate in water and methanol. Detection was performed using a triple quadrupole tandem mass spectrometer with electrospray ionization. Validation was performed in a range of 10–2500 μg/L for lorlatinib, 25–6250 μg/L for alectinib and crizotinib, 25–10,000 μg/L for capmatinib and selpercatinib, 50–12,500 μg/L for brigatinib, and 100–25,000 μg/L for adagrasib and sotorasib. Imprecision was <8.88% and inaccuracy was <12.5% for all compounds. Seven out of eight compounds were stable for 96 h at room temperature. Sotorasib was stable for 8 h at room temperature. A sensitive and reliable method has been developed to quantify eight SMIs with a single assay, enhancing efficacy and safety of targeted therapies.

show abstract

Development and validation of a robust and sensitive HPLC-MS/MS method for the quantitation of MRTX849 in plasma and its application in pharmacokinetics

Abstract: A novel, robust and sensitive HPLC-MS/MS method was firstly developed and fully validated for quantitating MRTX849 in plasma. This analytical method was successfully applied for a pharmacokinetic study of MRTX849 at a dose of 15 mg kg−1 in rats.

Cited by 5 publications

References 18 publications

Development and validation of an HPLC–MS/MS method to quantify the KRAS inhibitor adagrasib in mouse plasma and tissue‐related matrices

Development and validation of an HPLC–MS/MS method to quantify the KRAS inhibitor adagrasib in mouse plasma and tissue‐related matrices

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

Development and validation of an ultra‐performance liquid chromatography–tandem mass spectrometry method to quantify the small molecule inhibitors adagrasib, alectinib, brigatinib, capmatinib, crizotinib, lorlatinib, selpercatinib, and sotorasib in human plasma

Contact Info

Product

Resources

About