Quantification of Venetoclax for Therapeutic Drug Monitoring in Chinese Acute Myeloid Leukemia Patients by a Validated UPLC-MS/MS Method

Abstract

Venetoclax has emerged as a breakthrough for treatment of leukemia with a wide interindividual variability in pharmacokinetics. Herein, a rapid, sensitive, and reliable UPLC-MS/MS method for quantification of venetoclax in plasma was developed and validated. The method was operated in the multiple-reaction monitoring (MRM) mode to detect venetoclax at m/z transition 868.5 > 321.0 and IS at 875.5 > 321.0, respectively. Protein precipitation prior to injection into the LC-MS/MS and the analyte was separated on an ACQUITY UPLC BEH C18 column by gradient elution with acetonitrile and 0.1% formic acid in water. Linear calibration curves were obtained in the range of 25–8000 ng/mL. The specificity, recovery, matrix effect, and stability also met the acceptance criteria of FDA guidance. The method was successfully applied to analyze plasma in acute myeloid leukemia (AML) patients. The peak plasma concentration (Cmax) of venetoclax in Chinese AML patient was 2966.0 ± 1595.0 ng/mL while the trough concentration (Cmin) was 1018.0 ± 729.4 ng/mL. Additionally, Cmax and Cmin showed a positive correlation with AST levels. Furthermore, Cmax was significantly higher in the older patients. The present method can be applied for TDM of venetoclax in treatment of hematological cancers.

Venetoclax dose adjustment due to drug-drug interactions: a case report and literature review

“…Presently, research on monitoring serum Venetoclax concentration during treatment is still less. To our knowledge, there are only two methodological studies published [ 29 , 30 ], and no clinical intervention study is performed to prove the effect of serum drug concentration on treatment safety. Both the two existing studies reported that the steady-state trough concentration of Venetoclax during treatment in AML patients fluctuated in a range of 250–8000 ng/ml.…”

LC–MS/MS methods for determination of venetoclax in human plasma and cerebrospinal fluid

“…However, venetoclax has a high variability between patients with nonlinearity in relative bioavailability (Freise et al, 2017; Kaufman et al, 2021; Yang et al, 2022) and exhibits a severe drug–drug interaction with azole antifungals such as posaconazole (Bhatnagar et al, 2021). Therefore, it is necessary to monitor the plasma exposure of venetoclax in patients.…”

“…There are limited studies focusing on the transitivity of venetoclax to the cerebrospinal fluid (CSF), which needs to be evaluated to consider it as a treatment option for patients with central nervous system metastasis. Although an article (Yang et al, 2022) has focused on quantifying venetoclax in human plasma, there is a lack of reported analytical methods for assessing venetoclax in CSF. Therefore, we developed and validated methods using high sensitivity and specificity for determining venetoclax in human plasma and CSF using LC–MS/MS.…”

“…Although an article Yan-Ling Yang and Zhou-Yi Qian are co-first authors. (Yang et al, 2022) has focused on quantifying venetoclax in human plasma, there is a lack of reported analytical methods for assessing venetoclax in CSF. Therefore, we developed and validated methods using high sensitivity and specificity for determining venetoclax in human plasma and CSF using LC-MS/MS.…”

LC–MS/MS method for the quantitation of decitabine and venetoclax in rat plasma after SPE: Application to pharmacokinetic study

“…Few mass spectrometry-based methods, including liquid chromatography with tandem mass spectrometry (LC-MS/MS) have been published for the quantification of individually DCB ( Xu et al, 2012 , Liu et al, 2006 ) and VTX ( Yang et al, 2022 ) or in combination with other anti-cancer agents ( Reddy et al, 2021 , Sai Prudhvi et al, 2021 , Zhang et al, 2013 ). Bioanalytical method for determination of DCB and VTX in biological samples, have not yet been reported.…”