Drug design, development and therapy · 2025
Determination of Total and Free Plasma Concentration of Liposomal Mitoxantrone and Clinical Application in Adult Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma.
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Xu Yuxiang, Zhang Qi, Qie Hongxin, Gao Xiaonan, Gao Jinglin, Feng Zhangying, Wang Mingxia
Аннотация
PURPOSE: Currently reported methods for determining plasma concentration of mitoxantrone primarily measure total drug concentration. However, methodologies for quantifying liposomal mitoxantrone, particularly the free drug fraction, are lacking. Since the free drug represents the pharmacologically active moiety responsible for therapeutic effects, this study aimed to establish a detection method for total and free concentration of liposomal mitoxantrone in human plasma, while also exploring the temporal changes in drug concentration throughout the dosing cycle for liposomal mitoxantrone.
PATIENTS AND METHODS: For total mitoxantrone, the mobile phase consisted of 10 mmol/L KH2PO4 and methanol, UV detection was performed at a wavelength of 610 nm and protein precipitation was utilized as a pretreatment method. For free mitoxantrone, a gradient elution program in 6.5 min using the mobile phase that made up by 0.2% formic acid and 10mM ammonium acetate water (A) and acetonitrile (B) after a simple pretreatment by solid phase extraction. Sixty-eight total mitoxantrone samples from 35 patients and 61 free mitoxantrone samples from 31 patients with relapsed or refractory peripheral T-cell lymphoma who received intravenous infusions of liposomal mitoxantrone-based chemotherapy regimen were determined.
RESULTS: The linear calibration range of total and free mitoxantrone were 0.1-5 µg/mL and 5-500 ng/mL (r2> 0.99), respectively. Both intra- and inter-batch precision were less than 10.15%, and the accuracy ranged from 91.07% to 116.82%. The average total concentration in T-cell lymphoma patients after 12 hours of administration was 10.47 µg/mL, while the average free concentration was 272.22 ng/mL.
CONCLUSION: In this study, we established UPLC and UPLC-MS/MS methods for determining the total and free concentrations of liposomal mitoxantrone which were highly efficient, accurate, specific and suitable for clinical application and investigating the pharmacokinetics. Correlation analysis revealed that gender might be an important factor influencing the concentration of liposomal mitoxantrone in patients with relapsed or refractory peripheral T-cell lymphoma.
PATIENTS AND METHODS: For total mitoxantrone, the mobile phase consisted of 10 mmol/L KH2PO4 and methanol, UV detection was performed at a wavelength of 610 nm and protein precipitation was utilized as a pretreatment method. For free mitoxantrone, a gradient elution program in 6.5 min using the mobile phase that made up by 0.2% formic acid and 10mM ammonium acetate water (A) and acetonitrile (B) after a simple pretreatment by solid phase extraction. Sixty-eight total mitoxantrone samples from 35 patients and 61 free mitoxantrone samples from 31 patients with relapsed or refractory peripheral T-cell lymphoma who received intravenous infusions of liposomal mitoxantrone-based chemotherapy regimen were determined.
RESULTS: The linear calibration range of total and free mitoxantrone were 0.1-5 µg/mL and 5-500 ng/mL (r2> 0.99), respectively. Both intra- and inter-batch precision were less than 10.15%, and the accuracy ranged from 91.07% to 116.82%. The average total concentration in T-cell lymphoma patients after 12 hours of administration was 10.47 µg/mL, while the average free concentration was 272.22 ng/mL.
CONCLUSION: In this study, we established UPLC and UPLC-MS/MS methods for determining the total and free concentrations of liposomal mitoxantrone which were highly efficient, accurate, specific and suitable for clinical application and investigating the pharmacokinetics. Correlation analysis revealed that gender might be an important factor influencing the concentration of liposomal mitoxantrone in patients with relapsed or refractory peripheral T-cell lymphoma.