An Ultrasensitive LC-APPI-MS/MS Method for Simultaneous Determination of Ciclesonide and Active Metabolite Desisobutyryl-Ciclesonide in Human Serum and Its Application to a Clinical Study
An Ultrasensitive LC-APPI-MS/MS Method for Simultaneous Determination of Ciclesonide and Active Metabolite Desisobutyryl-Ciclesonide in Human Serum and Its Application to a Clinical Study
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DOI：
10.1373/jalm.2019.029397
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发表时间：
2020-01-01
影响因子：
2
通讯作者：
Sunkaraneni, Soujanya
中科院分区：
文献类型：
--
作者：
Chen, Yu-Luan;Wang, Weimin;Sunkaraneni, Soujanya
背景：为了开发更有效的环莱奈德吸入产品给药装置，需要一种超灵敏的生物分析方法来测量环莱奈德（CIC）及其活性代谢物去异丁基环莱奈德（des-CIC）在人体中的系统暴露。方法：用1-氯丁烷提取血清样品。采用反相液相色谱-常压光电离-串联质谱法（lc - api -MS/MS）对0.500 mL血清中1-500 pg/mL的两种分析物进行定量。分析时间为4.7 min/次。内标采用CIC-d（11）和des-CIC-d（11）。结果：两种分析物均具有良好的线性关系（r(2) > 0.99）。该方法精密度和准确度均在9.6% CV范围内，对常规QC样品的偏差为+/- 4.0%。两种分析物的萃取回收率约为85%。血清样品在3个冻融周期，24小时，以及在-20℃和-70℃下长达706天都是稳定的。该方法成功地用于支持健康参与者中环lesonide吸入悬浮液和吸入气雾剂之间的药代动力学（PK）比较。结果表明，该方法具有良好的再分析重现性。结论：APPI是一种高选择性、高灵敏度的电离源，可用于人血清中CIC和des-CIC的定量，定量下限（LLOQ）为1 pg/mL。与目前报道的最灵敏的方法（LLOQ, 10 pg/mL）相比，将灵敏度提高10倍对于充分表征CIC和des-CIC的PK谱至关重要，从而支持环lesonide相关药物的临床开发。
Background: The development of more efficient drug delivery devices for ciclesonide inhalation products requires an ultrasensitive bioanalytical method to measure systematic exposure of ciclesonide (CIC) and its active metabolite desisobutyryl-ciclesonide (des-CIC) in humans.Method: Serum sample was extracted with 1-chlorobutane. A reversed-phase liquid chromatography coupled with atmospheric pressure photoionization-tandem mass spectrometry (LC-APPI-MS/MS) method was used for quantification of 1-500 pg/mL for both analytes in a 0.500-mL serum. The analysis time was 4.7 min/injection. CIC-d(11) and des-CIC-d(11) were used as the internal standards.Results: Calibration curves showed good linearity (r(2) > 0.99) for both analytes. This novel method was precise and accurate with interassay precision and accuracy of all within 9.6% CV and +/- 4.0% bias for regular QC samples. Extraction recovery was approximately 85% for both analytes. Serum samples are stable for 3 freeze-thaw cycles, 24 h at bench top, and upto 706 days at both -20 degrees Cand-70 degrees C. This method was successfully used to support a pharmacokinetic (PK) comparison between the inhalation suspensions and an inhalation aerosol of ciclesonide in healthy participants. The method robustness was also supported by the good incurred sample reanalysis reproducibility.Conclusion: APPI, a highly selective and sensitive ionization source, made possible for quantifying CIC and des-CIC with a lower limit of quantification (LLOQ) of 1 pg/mL in human serum by LC-MS/MS. A 10-fold sensitivity improvement from the most sensitive reported method (LLOQ, 10 pg/mL) is essential to fully characterize the PK profiles of CIC and des-CIC in support of the clinical development of the ciclesonide-related medications for patients.