Method Establishment and Application for Bedaquiline Therapeutic Drug Motoring
Objective:To establish a method and apply it for the determination of plasma bedaquiline concentrations.Methods:Human plasma samples containing bedaquiline were spiked with sertraline as an internal standard.After protein precipitation with methanol,the samples were subjected to separation using a C18 chromatographic column with a gradient elution of methanol and 10 mmol·L-1 ammonium formate solu-tion.Detection was performed using electrospray ionization,and multiple reaction monitoring(MRM)was employed for the quantitative determination of bedaquiline and sertraline,with ion transitions at m/z 555.2→229.0 and m/z 306.2→159.0,respectively.Results:The linear range for the determination of be-daquiline was found to be 0.010 to 3.0 μg·mL-1(r=0.9995),with a quantification limit of 0.010 μg·mL-1.The validated method conformed to the requirements for analysis of biological samples.For the monitoring of bedaquiline blood concentrations during treatment in six multidrug-resistant tuberculosis(MDR-TB)pa-tients,the peak plasma concentration(Cmax)of bedaquiline on the 7th day of treatment was(3.48±0.70)μg·mL-1,with a time to peak concentration(tmax)of(5.33±1.03)hours,and a half-life(t1/2)of(18.73±6.39)hours.The area under the concentration-time curve(AUClast)was 50.16±9.74 μg·h·mL-1,and the mean residence time(MRT)was(10.62±0.69)hours.The apparent clearance(CL/F)was(4.83±1.34)L·h-1,and the apparent volume of distribution(V/F)was(123.55±24.19)L.Conclusions:The established LC-MS/MS analysis method has good specificity,high sensitivity,accuracy and precision,and can be used to determine bedaquiline plasma concentrations in MDR-TB patients.
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