Development and Validation of a Novel UHPLC-MS/MS Method for the Quantification of Plinabulin in Plasma and Its Application in a Pharmacokinetic Study with Leukopenic Rats

by Selleckchem | Dec 25 2023

Plinabulin, a new antitumor drug developed from marine natural products that targets microtubules in cancer cells, is currently being tested in a phase III clinical study. Plinabulin has been clinically proven to be effective on leukopenia. However, to our knowledge, there are no reports investigating the pharmacokinetics of plinabulin in individuals with leukopenia and healthy individuals. In this study, we developed a rapid and sensitive UHPLC-MS/MS method for the detection of plinabulin for the first time. Using a novel cyclophosphamide-induced leukopenia model, we investigated the differences in the pharmacokinetic characteristics of plinabulin between rats with leukopenia and normal rats. Plinabulin and propranolol (IS) peaks were separated by gradient elution for a total run time of 5 min. The methodological validation showed a good accuracy (101.96-109.42%) and precision (RSD ≤ 5.37%) with the lower limit of quantification at 0.5 ng/mL. The recovery of plinabulin was between 91.99% and 109.75% (RSD ≤ 7.92%). The values of the area under the plasma concentration-time curve (AUC0-t) for leukopenia groups and control groups at doses of 0.5 mg/kg, 1 mg/kg, and 3 mg/kg were 148.89 ± 78.74 h·μg/L and 121.75 ± 31.56 h·μg/L; 318.15 ± 40.00 h·μg/L and 272.06 ± 42.85 h·μg/L; and 1432.43 ± 197.47 h·μg/L and 1337.12 ± 193.56 h·μg/L; respectively. The half-lives (t1/2s) of plinabulin were 0.49-0.72 h for leukopenia groups and 0.39-0.70 h for control groups at three doses, and the clearance rates (CLs) of plinabulin were 2.13-3.87 L/h/kg for leukopenia groups and 2.29-4.23 L/h/kg for control groups. Pharmacokinetic results showed that there was no significant pharmacokinetic difference between the normal group and the leukopenia group. Based on the power model, plinabulin exhibits a lack of dose proportionality over the dose range of 0.5-3 mg/kg after intravenous administration. This study provides guidance for the development of plinabulin as a potential candidate for the treatment of chemotherapy-induced leukopenia.

Comments:

It sounds like the study you're referring to is investigating the pharmacokinetics of plinabulin in both normal rats and those with induced leukopenia. The aim seems to be to understand if there are any differences in how the drug behaves in these two conditions.

The methodological approach, utilizing UHPLC-MS/MS for detecting plinabulin and propranolol as the internal standard, appears to be robust. Achieving a good accuracy, precision, and recovery rate during method validation is crucial for ensuring the reliability of the results obtained.

The pharmacokinetic data, specifically the area under the plasma concentration-time curve (AUC), half-lives (t1/2s), and clearance rates (CLs) of plinabulin at different doses in both leukopenia and control groups, were outlined. Interestingly, despite the study's premise, the results suggest no significant pharmacokinetic differences between the two groups.

The conclusion that plinabulin exhibits a lack of dose proportionality over the tested dose range is intriguing and important for understanding its behavior at various dosage levels. This finding could have implications for its optimal dosing strategies in clinical settings.

The implications for the treatment of chemotherapy-induced leukopenia are significant. If plinabulin demonstrates efficacy against leukopenia without impacting its pharmacokinetics, it could potentially become a valuable candidate for managing this chemotherapy-related side effect.

However, it's crucial to remember that this study is conducted on rats, and extrapolating these findings directly to human patients would require further clinical trials and investigations. Understanding the safety and efficacy profile in humans with leukopenia is a crucial next step in considering plinabulin's clinical application for this condition.