Quantification of Venetoclax for Therapeutic Drug Monitoring in Chinese Acute Myeloid Leukemia Patients by a Validated UPLC-MS/MS Method
Abstract
:1. Introduction
2. Results and Discussion
2.1. Method Development and Optimization
2.2. Method Validation
2.2.1. Linearity, Selectivity and Specificity
2.2.2. Precision and Accuracy
2.2.3. Recovery and Matrix Effect
2.2.4. Carry-Over
2.2.5. Stability
2.3. Patient Characteristics and Venetoclax Concentrations
2.4. Relationship between Covariates and Venetoclax Concentrations
3. Material and Methods
3.1. Chemicals and Reagents
3.2. Calibrators and QCs
3.3. Sample Preparation
3.4. UPLC-MS/MS Conditions
3.5. Method Validation
3.5.1. Calibration Curve, Selectivity and Specificity
3.5.2. Precision and Accuracy
3.5.3. Matrix Effect and Recovery
3.5.4. Carry-Over
3.5.5. Stability
3.6. Application
3.7. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound | Retention Time (tR, min) | Transition (m/z) | Cone Voltage (V) | Collision Energy (V) | |
---|---|---|---|---|---|
Quantification | Confirmation | ||||
venetoclax | 1.8 | 868.5→321.0 | 868.5→636.3 | 70 | 36 |
IS | 1.8 | 875.5→321.0 | 875.5→636.3 | 60 | 40 |
Compound | Concentration Spiked (ng/mL) | Intra-Day Concentration Measured (ng/mL) | Accuracy RE (%) | Precision RSD (%) | Inter-Day Concentration Measured (ng/mL) | Accuracy RE (%) | Precision RSD (%) |
---|---|---|---|---|---|---|---|
Venetoclax | 25 | 24.80 ± 0.57 | −0.80 | 2.28 | 25.12 ± 1.64 | 0.49 | 6.51 |
50 | 51.35 ± 3.17 | 2.70 | 6.18 | 48.44 ± 3.54 | −3.11 | 7.30 | |
2500 | 2523.77 ± 89.95 | 0.95 | 3.56 | 2419.72 ± 122.66 | −3.21 | 5.07 | |
6000 | 5609.22 ± 111.53 | −6.51 | 1.99 | 5711.31 ± 235.93 | −4.81 | 4.13 |
Compound | Concentration Spiked (ng/mL) | Recovery (%) | Matrix Effect (%) | ||
---|---|---|---|---|---|
Mean ± SD | RSD% | Mean ± SD | RSD% | ||
Venetoclax | 50 | 108.36 ± 2.63 | 2.63 | 89.77 ± 4.78 | 5.33 |
2500 | 106.24 ± 1.93 | 1.82 | 89.36 ± 3.38 | 3.78 | |
6000 | 106.64 ± 5.73 | 5.37 | 91.12 ± 2.02 | 2.21 | |
IS | 1000 | 104.41 ± 2.76 | 2.62 | 90.19 ± 2.34 | 2.60 |
Spiked (ng/mL) | Condition | Found (ng/mL, Mean ± SD) | Precision RSD (%) | Accuracy RE (%) |
---|---|---|---|---|
50 | Room temperature for 6 h | 45.67 ± 1.12 | 2.4 | −8.66 |
−80 °C for 31 days | 49.57 ± 1.15 | 2.3 | −0.87 | |
Three freeze-thaw cycles | 48.77 ± 1.53 | 3.1 | −5.38 | |
Autosampler in 4 °C for 8 h | 46.70 ± 2.13 | 4.6 | −6.60 | |
6000 | Room temperature for 6 h | 6045.47 ± 152.82 | 2.5 | 0.76 |
−80 °C for 31 days | 5618.17 ± 56.22 | 1.0 | −6.36 | |
Three freeze-thaw cycles | 5676.83 ± 71.15 | 1.3 | −2.5 | |
Autosampler in 4 °C for 8 h | 5800.63 ± 168.44 | 2.9 | −3.32 |
Characteristic | Mean (±SD) | Median (Range) |
---|---|---|
Age (year) | 58.9 ± 14.3 | 62 (18.0–90.0) |
Height (cm) | 165.5 ± 5.5 | 165.0 (153.0–177.0) |
Weight (kg) | 63.44 ± 10.48 | 62.25 (43.5–92.0) |
BMI (kg/m2) | 23.1 ± 3.3 | 23.0 (16.9–31.46) |
Gender (Female/Male) | 26/36 | |
ALB (g/L) | 40.1 ± 5.65 | 40.85 (25.7–51) |
ALT (U/L) | 15.08 ± 8.65 | 14 (3–54) |
AST (U/L) | 20.45 ± 10.66 | 17 (4–62) |
BUN (mmol/L) | 5.83 ± 2.61 | 5.41 (1.94–18.70) |
CREA (µmol/L) | 77.4 ± 30.6 | 69.5 (42.0–224.0) |
LDH (U/L) | 358 ± 325.1 | 234.5 (54–2066) |
WBC (10^9/L) | 9.37 ± 14.34 | 3.94 (0.77–83.59) |
NEUT (10^9/L) | 2.60 ± 5.21 | 1.485 (0.06–31.29) |
HGB (g/L) | 86.4 ± 24.85 | 83 (45–137) |
PLT (10^9/L) | 85.18 ± 151.9 | 33.5 (3–1097) |
Cmax (ng/mL, n = 61) | 2966.0 ± 1595.0 | 2408.0 (515.4–7189.0) |
Cmin (ng/mL, n = 48). | 1018.0 ± 729.4 | 836.6 (74.2–3257.0) |
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Yang, X.; Mei, C.; He, X.; He, L.; Lu, X.; Tong, H.; Lou, Y. Quantification of Venetoclax for Therapeutic Drug Monitoring in Chinese Acute Myeloid Leukemia Patients by a Validated UPLC-MS/MS Method. Molecules 2022, 27, 1607. https://doi.org/10.3390/molecules27051607
Yang X, Mei C, He X, He L, Lu X, Tong H, Lou Y. Quantification of Venetoclax for Therapeutic Drug Monitoring in Chinese Acute Myeloid Leukemia Patients by a Validated UPLC-MS/MS Method. Molecules. 2022; 27(5):1607. https://doi.org/10.3390/molecules27051607
Chicago/Turabian StyleYang, Xi, Chen Mei, Xiaoying He, Lingjuan He, Xiaoyang Lu, Hongyan Tong, and Yan Lou. 2022. "Quantification of Venetoclax for Therapeutic Drug Monitoring in Chinese Acute Myeloid Leukemia Patients by a Validated UPLC-MS/MS Method" Molecules 27, no. 5: 1607. https://doi.org/10.3390/molecules27051607