| Objective To study the pharmacokinetics, pharmacodynamics of bendamustine in Chinese indolent B-cell non-Hodgkin's lymphoma patients, and to evaluate the influence of SLC22A1,CYP1A2, GSTA1 polymorphism on plasma concentration of bendamustine.Methods 1 A method of ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) for the determination of bendamustine concentration in plasma was developed, and the methodology was assayed including the specificity, matrix effect, sensitivity, precision, average recovery ratio, stability and dilution effect.2 Applying the design, 14 patients were enrolled for the clinical trial. bendamustine hydrochloride 120 mg/m2/d was administered intravenously in 120 min on days 1 and 2 every 3 weeks. 4 m L blood samples were obtained at predetermined time points before(0 h),during(1 h,2 h) and after bendamustine hydrochloride administation, which is 5 min, 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, which was used for determining the bendamustine concentration in plasma. The primary pharmacokinetic parameters were t1/2, Cl?Vd, AUC that were caculated using DAS2.0.3 Applying the design, 21 patients were enrolled for Phase ? trial to study the pharmacodynamics of bendamustine. Bendamustine hydrochloride was administered as a 240-min intravenous infusion with a dose of 120 mg/m2/d, after bendamustine administation(4 h,24 h), 4 m L blood samples were obtained for the determination of bendamustine concentration. 4 DNA extraction was carried out on 200 ?l of plasma by using QIAamp DNA blood kit. Subjects were genotyped for SLC22A1(rs200684404, rs4646277,rs2282143,rs628031,rs35167514,rs622342), CYP1A2(rs762551, rs2069514, rs2470890,rs2472304,rs12720461), GSTA1(rs3957356,rs3957357) alleles by direct sequencing. We statistically analyzed associations between polymorphisms in SLC22A1,CYP1A2 and GSTA1 with plasma concentration of bendamustine.Results 1 A simple, rapid UPLC-MS/MS method was developed for the quantification of bendamustine in human plasma and the specificity, sensitivity,precision, average recovery ratio, stability, dilution effect and matrix effect all satisfied the pharmacokinetic detection requirements. The assay demonstrated linearity from 5 to 1000 ug/L bendamustine in plasma. 2 The main pharmacodynamic parameters of bendamustine: Cmax is 4822.571±3477.123 ug/L;CL is 25.75±15.198 L/h/m2; t1/2 is 0.388±0.157 h; AUC(0-?) is 6463.691±3859.084 ug/L*h.3 The aim of this study was to evaluate the efficacy profile of bendamustine. CR, PR was found in 12.5%, 50.0%, respectively, and SD was noted in 3 patients(18.8%).4 In our work, only SLC22A1(rs683369?rs2282143?rs628031?rs622342),CYP1A2(rs762551?rs2069514?rs2472304? rs2470890) exist SNPs. We didn't find there are associations between polymorphisms in SLC22A1,CYP1A2 with plasma concentration of bendamustine.Conclusions 1 The developed UPLC-MS/MS method was successfully applied to study a pharmacokinetic in indolent B-cell non-Hodgkin's lymphoma patients after administrated bendamustine.2 Bendamustine was rapidly eliminated. 3 In Chinese patients, bendamustine treatment was of acceptable efficacy in patients with indolent B-cell non-Hodgkin's lymphoma.4 The reason that there are no associations between polymorphisms in SLC22A1,CYP1A2 with bendamustine plasma concentration of bendamustine maybe is the sample size too small. |
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