Development of Simultaneous Drug Concentration Measurement Method Using an Automated Pretreatment Liquid Chromatography/Tandem Mass Spectrometry System for Therapeutic Drug Monitoring
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Reagents
2.2. Preparation of Stock Solutions, Working Solutions, Calibration Standard Samples, and Quality Control Samples
2.3. Sample Preparation
2.3.1. Automated Method (CLAM Method)
2.3.2. Manual Pretreatment Method
2.4. LC-MS/MS Conditions
2.5. Validation
2.6. Measurement of Patient Samples
2.7. Data Analysis
3. Results and Discussion
3.1. Development and Validation of the CLAM Method
3.2. Method Comparison
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sample | Clozapine (ng/mL) | Mycophenolic Acid (µg/mL) | Sunitinib (ng/mL) | N-Desethylsunitinib (ng/mL) | Voriconazole (µg/mL) |
---|---|---|---|---|---|
CS1 | 30 | 0.2 | 1 | 1 | 0.1 |
CS2 | 60 | 0.4 | 2 | 2 | 0.2 |
CS3 | 150 | 1 | 5 | 5 | 0.5 |
CS4 | 750 | 5 | 25 | 25 | 2.5 |
CS5 | 1500 | 10 | 50 | 50 | 5 |
CS6 | 3000 | 20 | 100 | 100 | 10 |
LLOQ | 30 | 0.2 | 1 | 1 | 0.1 |
LQC | 100 | 0.66 | 3.3 | 3.3 | 0.33 |
MQC | 300 | 2 | 10 | 10 | 1 |
HQC | 1000 | 6.6 | 33 | 33 | 3.3 |
Compound | Type | SRM Transition (m/z) | Q1 (V) | CE (V) | Q3 (V) | Q-Array Bias (V) | RT (min) | IS |
---|---|---|---|---|---|---|---|---|
Clozapine | Analyte | 328.70 > 272.10 | −23.0 | −23.0 | −19.0 | - | 2.03 | Clozapine-d8 |
Clozapine-d8 | IS | 336.90 > 276.10 | −24.0 | −24.0 | −30.0 | - | 2.02 | - |
Mycophenolic acid | Analyte | 321.40 > 207.00 | −11.0 | −20.0 | −22.0 | - | 2.48 | Mycophenolic acid-d3 |
Mycophenolic acid-d3 | IS | 324.05 > 210.05 | −16.0 | −22.0 | −22.0 | - | 2.48 | - |
Sunitinib | Analyte | 399.10 > 283.05 | −20.0 | −28.0 | −20.0 | - | 2.10 | Sunitinib-d10 |
N-desethylsunitinib | Analyte | 371.10 > 283.10 | −19.0 | −22.0 | −20.0 | - | 2.05 | Sunitinib-d10 |
Sunitinib-d10 | IS | 409.50 > 283.55 | −13.0 | −24.0 | −10.0 | - | 2.11 | - |
Voriconazole | Analyte | 349.85 > 281.10 | −13.0 | −16.0 | −13.0 | 100 | 2.40 | Voriconazole-d3 |
Voriconazole-d3 | IS | 352.90 > 284.10 | −13.0 | −17.0 | −20.0 | - | 2.40 | - |
Analyte | Range | Calibration Regression Curves | R2 |
---|---|---|---|
Clozapine | 30–3000 ng/mL | y = 0.0017x − 0.0017 | 0.9986 |
Mycophenolic acid | 0.2–20 µg/mL | y = 0.1741x − 0.0056 | 0.9993 |
Sunitinib | 1–100 ng/mL | y = 0.0668x + 0.0175 | 0.9989 |
N-desethylsunitinib | 1–100 ng/mL | y = 0.0833x + 0.0337 | 0.9976 |
Voriconazole | 0.1–10 µg/mL | y = 0.2430x + 0.0046 | 0.9978 |
Analyte | Intra-Day (n = 5) | Inter-Day (n = 15) | ||
---|---|---|---|---|
RE (%) | CV (%) | RE (%) | CV (%) | |
Clozapine | ||||
LLOQ | 6.2 | 2.8 | 7.4 | 5.7 |
LQC | −1.6 | 1.2 | −0.4 | 3.0 |
MQC | 0.1 | 1.1 | −3.0 | 4.2 |
HQC | 1.2 | 0.7 | 1.3 | 3.7 |
Mycophenolic acid | ||||
LLOQ | 11.3 | 5.1 | 11.2 | 3.8 |
LQC | −2.8 | 2.7 | 1.6 | 4.6 |
MQC | −5.1 | 2.2 | −2.7 | 3.8 |
HQC | −5.7 | 2.8 | 0.7 | 5.9 |
Sunitinib | ||||
LLOQ | −10.7 | 5.8 | −1.2 | 9.9 |
LQC | −4.1 | 4.2 | 0.9 | 7.2 |
MQC | 4.3 | 2.2 | 0.8 | 6.7 |
HQC | −0.4 | 0.8 | −1.5 | 8.2 |
N-desethylsunitinib | ||||
LLOQ | −14.8 | 8.8 | −4.2 | 10.5 |
LQC | −2.9 | 2.2 | −0.5 | 6.2 |
MQC | 3.8 | 2.3 | 3.0 | 5.2 |
HQC | −0.1 | 1.4 | 0.8 | 5.7 |
Voriconazole | ||||
LLOQ | −2.6 | 3.1 | −5.4 | 8.2 |
LQC | 2.4 | 1.2 | 4.6 | 3.8 |
MQC | 4.6 | 1.9 | 5.9 | 5.1 |
HQC | 3.5 | 1.6 | 7.4 | 4.8 |
Condition | Clozapine | Mycophenolic Acid | Sunitinib | N-Desethylsunitinib | Voriconazole | |||||
---|---|---|---|---|---|---|---|---|---|---|
RE (%) | CV (%) | RE (%) | CV (%) | RE (%) | CV (%) | RE (%) | CV (%) | RE (%) | CV (%) | |
Room temperature for 24 h | ||||||||||
LQC | −13.1 | 6.2 | −0.8 | 2.8 | 5.9 | 4.5 | 8.1 | 3.3 | −5.4 | 3.6 |
MQC | −5.6 | 3.2 | 6.4 | 6.7 | 7.2 | 5.4 | 10.9 | 4.5 | 8.5 | 5.2 |
HQC | −11.0 | 6.0 | −6.8 | 4.3 | 1.1 | 6.4 | 5.5 | 3.7 | −3.4 | 2.8 |
4 °C for 24 h | ||||||||||
LQC | −3.1 | 1.6 | 0.3 | 1.9 | 1.2 | 3.2 | −1.2 | 7.4 | 1.6 | 0.9 |
MQC | −8.4 | 4.0 | −5.4 | 2.5 | −3.5 | 6.1 | 5.4 | 5.5 | 0.5 | 0.9 |
HQC | −3.1 | 1.8 | −0.7 | 0.8 | −1.8 | 7.4 | 3.4 | 7.2 | 4.5 | 1.9 |
4 °C for 28 days | ||||||||||
LQC | −7.0 | 5.5 | −6.7 | 5.0 | −3.3 | 4.1 | 1.4 | 1.9 | −3.0 | 5.5 |
MQC | −12.3 | 6.5 | −10.6 | 5.8 | −9.6 | 5.1 | −0.2 | 2.2 | −4.3 | 3.9 |
HQC | −9.4 | 5.8 | −7.6 | 6.2 | −1.8 | 3.7 | 4.2 | 4.1 | −2.2 | 3.9 |
Analyte | Intercept (95% CI) | Slope (95% CI) | Significance (CUSUM Test for Linearity) | Correlation (r) | Significance (Spearman’s Correlation) |
---|---|---|---|---|---|
Clozapine | −5.49 (−49.68–23.59) | 1.04 (0.97–1.13) | 0.82 | 0.978 | <0.0001 |
Mycophenolic acid | −0.03 (−0.08–0.06) | 1.01 (0.97–1.03) | 0.99 | 0.997 | <0.0001 |
Sunitinib | −0.53 (−4.90–0.68) | 1.01 (0.98–1.11) | 0.82 | 0.937 | <0.0001 |
N-desethylsunitinib | −0.24 (−1.45–0.35) | 1.03 (0.99–1.11) | 0.99 | 0.969 | <0.0001 |
Voriconazole | −0.01 (−0.06–0.05) | 0.99 (0.95–1.04) | 0.82 | 0.995 | <0.0001 |
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Sato, Y.; Kondo, H.; Sato, Y.; Abe, A.; Kikuchi, M.; Sato, T.; Kumondai, M.; Yoshikawa, K.; Hayakawa, Y.; Maekawa, M.; et al. Development of Simultaneous Drug Concentration Measurement Method Using an Automated Pretreatment Liquid Chromatography/Tandem Mass Spectrometry System for Therapeutic Drug Monitoring. Pharmaceutics 2024, 16, 1138. https://doi.org/10.3390/pharmaceutics16091138
Sato Y, Kondo H, Sato Y, Abe A, Kikuchi M, Sato T, Kumondai M, Yoshikawa K, Hayakawa Y, Maekawa M, et al. Development of Simultaneous Drug Concentration Measurement Method Using an Automated Pretreatment Liquid Chromatography/Tandem Mass Spectrometry System for Therapeutic Drug Monitoring. Pharmaceutics. 2024; 16(9):1138. https://doi.org/10.3390/pharmaceutics16091138
Chicago/Turabian StyleSato, Yu, Hiroki Kondo, Yuji Sato, Ai Abe, Masafumi Kikuchi, Toshihiro Sato, Masaki Kumondai, Kohei Yoshikawa, Yoshihiro Hayakawa, Masamitsu Maekawa, and et al. 2024. "Development of Simultaneous Drug Concentration Measurement Method Using an Automated Pretreatment Liquid Chromatography/Tandem Mass Spectrometry System for Therapeutic Drug Monitoring" Pharmaceutics 16, no. 9: 1138. https://doi.org/10.3390/pharmaceutics16091138