Pomalidomide is an immunomodulatory agent (IMiD) that has been approved by the US Food and Drug Administration (FDA) for clinical treatment of patients with multiple myeloma.In this work,we developed a sensitive and v...Pomalidomide is an immunomodulatory agent (IMiD) that has been approved by the US Food and Drug Administration (FDA) for clinical treatment of patients with multiple myeloma.In this work,we developed a sensitive and validated LC-MS/MS method for high-throughput determination of pomalidomide over the range of 1.006-100.6 ng/mL(R^(2)=0.9991) in human plasma and pharmacokinetic studies.A liquid-liquid extraction method using ethyl acetate was applied to extract pomalidomide and afatinib (as an internal standard,IS) from human plasma.Chromatographic separation was performed on a Hedera ODS column (150 mm×2.1 mm,5μm) with security guard C18 column (4 mm×2.0 mm) at 40℃.Methanol and 10 mmol/L aqueous solution of ammonium acetate containing 0.1%formic acid were used as a gradient elution mobile phase,and the flow rate was 0.4 mL/min.A triple quadruple tandem mass spectrometer using multiplex reaction monitoring mode (MRM) with electrospray ionization (ESI) positive ionization was employed.The precursor to product ion transitions for the quantitative analysis of pomalidomide and the IS were m/z 274.2→163.1 and m/z 486.1→371.1,respectively.This established method has been validated according to regulatory guideline,and the results were all within the acceptance criteria.The validated LC-MS/MS method was successfully applied to analyze samples obtained from clinical pharmacokinetics study after oral administration of pomalidomide (4 mg) capsules in human.展开更多
Preferential solvation of pomalidomide(PMD)was explored in dimethyl sulfoxide(DMSO)-dimethylformamide(DMF),DMSO-tetrahydrofuran(THF),DMSO-methanol(Me OH),DMSO-isopropanol,DMSO-water,water-DMF,water-THF,water-Me OH,and...Preferential solvation of pomalidomide(PMD)was explored in dimethyl sulfoxide(DMSO)-dimethylformamide(DMF),DMSO-tetrahydrofuran(THF),DMSO-methanol(Me OH),DMSO-isopropanol,DMSO-water,water-DMF,water-THF,water-Me OH,and water–isopropanol binary mixed solvents at 298.15 K.Bosch-Rose model was utilized to determine the electronic transition energies(ET)and other preferential solvation parameters,describing solute-solute and solute-solvent interactions.We found thatλmaxsituation shifted with dielectric constant of the pure solvents meaningfully.According to the obtained results,ETenhanced andλmaxshifted to the lower wavelengths as the percentage of DMSO decreased in the binary mixtures,remarking the important role of DMSO for stabilizing the excited state(π*)of PMD chromophore via efficient intermolecular solute-solvent interactions.In addition,the aqueous binary systems showed an optimum point for the ETvalues as the percentage of water changed in the solutions.The local mole fraction of the solvents in the cybotactic region was also estimated to describe the specific and non-specific interactions in the systems.展开更多
Relapsed and refractory multiple myeloma(RRMM)and B-cell leukemia/lymphoma with extramedullary disease(EMD)have poor prognosis and high mortality,lack of effective therapeutic approaches.We reported for the first time...Relapsed and refractory multiple myeloma(RRMM)and B-cell leukemia/lymphoma with extramedullary disease(EMD)have poor prognosis and high mortality,lack of effective therapeutic approaches.We reported for the first time that 6 patients with malignant hematological diseases with EMD received chimeric antigen receptor(CAR)-T treatment combined with pomalidomide,and CAR-T cells were treated with pomalidomide in vitro to determine its killing activity and cytokine secretion.Three patients with RRMM were given B cell maturation antigen(BCMA)-CAR-T therapy.All 3 patients with B-cell leukemia/lymphoma received CD19/22-CAR-T sequential infusion.There were no treatment-related deaths.The maximum overall response rate(ORR)was 100%.Median follow-up was 211.5 days(75–407 days).Three patients(50%)experienced cytokine release syndrome,all of which were grade 1,and no neurotoxicity was observed.In vitro experiments showed that the killing activity did not differ significantly between BCMA-CAR-T cells with and without pomalidomide(10,25,or 50μg/mL)in 8226/U266 cell cocultures(P>.05).Tumor necrosis factor(TNF)-αand interferon(IFN)-γsecretion was significantly higher from 8226 and Raji cells cocultured with BCMA-CAR-T and cluster of differentiation(CD)19-CAR-T cells(P<.05).Based on the cocultures,adding pomalidomide significantly promoted IFN-γand TNF-αsecretion(P<.05).Based on the above clinical and in vitro studies demonstrating the co-administration of pomalidomide with CAR-T cell treatment demonstrated favorable tolerability and therapeutic effectiveness in RRMM or B-cell leukemia/lymphoma.展开更多
基金financial support from National Natural Science Foundation of China (No.81603072)。
文摘Pomalidomide is an immunomodulatory agent (IMiD) that has been approved by the US Food and Drug Administration (FDA) for clinical treatment of patients with multiple myeloma.In this work,we developed a sensitive and validated LC-MS/MS method for high-throughput determination of pomalidomide over the range of 1.006-100.6 ng/mL(R^(2)=0.9991) in human plasma and pharmacokinetic studies.A liquid-liquid extraction method using ethyl acetate was applied to extract pomalidomide and afatinib (as an internal standard,IS) from human plasma.Chromatographic separation was performed on a Hedera ODS column (150 mm×2.1 mm,5μm) with security guard C18 column (4 mm×2.0 mm) at 40℃.Methanol and 10 mmol/L aqueous solution of ammonium acetate containing 0.1%formic acid were used as a gradient elution mobile phase,and the flow rate was 0.4 mL/min.A triple quadruple tandem mass spectrometer using multiplex reaction monitoring mode (MRM) with electrospray ionization (ESI) positive ionization was employed.The precursor to product ion transitions for the quantitative analysis of pomalidomide and the IS were m/z 274.2→163.1 and m/z 486.1→371.1,respectively.This established method has been validated according to regulatory guideline,and the results were all within the acceptance criteria.The validated LC-MS/MS method was successfully applied to analyze samples obtained from clinical pharmacokinetics study after oral administration of pomalidomide (4 mg) capsules in human.
文摘Preferential solvation of pomalidomide(PMD)was explored in dimethyl sulfoxide(DMSO)-dimethylformamide(DMF),DMSO-tetrahydrofuran(THF),DMSO-methanol(Me OH),DMSO-isopropanol,DMSO-water,water-DMF,water-THF,water-Me OH,and water–isopropanol binary mixed solvents at 298.15 K.Bosch-Rose model was utilized to determine the electronic transition energies(ET)and other preferential solvation parameters,describing solute-solute and solute-solvent interactions.We found thatλmaxsituation shifted with dielectric constant of the pure solvents meaningfully.According to the obtained results,ETenhanced andλmaxshifted to the lower wavelengths as the percentage of DMSO decreased in the binary mixtures,remarking the important role of DMSO for stabilizing the excited state(π*)of PMD chromophore via efficient intermolecular solute-solvent interactions.In addition,the aqueous binary systems showed an optimum point for the ETvalues as the percentage of water changed in the solutions.The local mole fraction of the solvents in the cybotactic region was also estimated to describe the specific and non-specific interactions in the systems.
基金the National Natural Science Foundation of China,grant number 82070217(Jia Wei)supported by 2023 COVID-19 Emergency Project of Shanxi Bethune Hospital(no.2023xg02,Dr.Weiwei Tian)Fundamental Research Program of Shanxi Province(no.202303021211224,Weiwei Tian).
文摘Relapsed and refractory multiple myeloma(RRMM)and B-cell leukemia/lymphoma with extramedullary disease(EMD)have poor prognosis and high mortality,lack of effective therapeutic approaches.We reported for the first time that 6 patients with malignant hematological diseases with EMD received chimeric antigen receptor(CAR)-T treatment combined with pomalidomide,and CAR-T cells were treated with pomalidomide in vitro to determine its killing activity and cytokine secretion.Three patients with RRMM were given B cell maturation antigen(BCMA)-CAR-T therapy.All 3 patients with B-cell leukemia/lymphoma received CD19/22-CAR-T sequential infusion.There were no treatment-related deaths.The maximum overall response rate(ORR)was 100%.Median follow-up was 211.5 days(75–407 days).Three patients(50%)experienced cytokine release syndrome,all of which were grade 1,and no neurotoxicity was observed.In vitro experiments showed that the killing activity did not differ significantly between BCMA-CAR-T cells with and without pomalidomide(10,25,or 50μg/mL)in 8226/U266 cell cocultures(P>.05).Tumor necrosis factor(TNF)-αand interferon(IFN)-γsecretion was significantly higher from 8226 and Raji cells cocultured with BCMA-CAR-T and cluster of differentiation(CD)19-CAR-T cells(P<.05).Based on the cocultures,adding pomalidomide significantly promoted IFN-γand TNF-αsecretion(P<.05).Based on the above clinical and in vitro studies demonstrating the co-administration of pomalidomide with CAR-T cell treatment demonstrated favorable tolerability and therapeutic effectiveness in RRMM or B-cell leukemia/lymphoma.
