Validation of Liquid Chromatography Coupled with Tandem Mass Spectrometry for the Determination of 12 Tyrosine Kinase Inhibitors (TKIs) and Their Application to Therapeutic Drug Monitoring in Adult and Pediatric Populations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials and Reagents
2.2. Calibration Standards and Quality Controls
2.3. Sample Preparation
2.4. Instrumental Analysis
2.5. Method Validation
2.5.1. Limits of Detection and Quantification
2.5.2. Linearity
2.5.3. Accuracy and Precision
2.5.4. Selectivity and Carryover
2.5.5. Matrix Effect and Recovery
2.5.6. Stability
2.6. Application
2.6.1. Population
2.6.2. Sample Collection
2.6.3. Statistical Analysis
3. Results
3.1. Method Validation
3.2. TKIs Plasma Concentrations
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Molecule | Target (TK) | Indication (Adults) | Target Concentrations (ng/mL) | Reference |
---|---|---|---|---|
Dabrafenib | BRAF | melanoma BRAF+ NSCLC BRAF+ | Cmin ≥ 15 | [21] |
Trametinib | MEK | melanoma BRAF+ NSCLC BRAF+ | Cmin ≥ 10.6 | [22] |
Binimetinib | MEK | melanoma BRAF+ | Cmax = 654 | [23] |
Cobimetinib | MEK 1/2 | melanoma BRAF+ | Cmax = 270 | [24] |
Encorafenib | BRAF | melanoma BRAF+ metastatic colorectal cancer | Cmax = 3100 | [25] |
Osimertinib | EGFFR | NSCLC EGFR+ | Cmin ≥ 90 (40 mg dosage) Cmin ≥ 160 (80 mg dosage) | [26] |
AZ5104 (metabolite) | EGFR | - | ||
Crizotinib | ALK | NSCLC ALK+ ou ROS1+ | Cmin ≥ 235 | [27] |
Alectinib | ALK, RET | NSCLC ALK+ | Cmin ≥ 570 | [28] |
Alectinib M4 (metabolite) | ALK | Cmin ≥ 220 | [28] | |
Imatinib | Bcr-Abl, c-Kit, PDGFR, SCFR, DDR | Chronic myeloid leukemia Acute lymphocytic leukemia Gastrointestinal stromal tumor Myelodysplastic/myeloproliferative syndromes | Cmin ≥ 1100 | [29] |
Lorlatinib | ALK ROS1 | NSCLC ALK+ | Cmax = 575 | [30] |
Molecules | G1 | G2 | G3 | G4 | G5 | G6 | G7 | QC1 | QC2 | QC3 | QC4 |
---|---|---|---|---|---|---|---|---|---|---|---|
AZ5104 (Osimertinib metabolite) | 0.2 | 1 | 2 | 10 | 20 | 100 | 200 | 0.3 | 3 | 15 | 150 |
Trametinib | |||||||||||
Alectinib | 2 | 10 | 20 | 100 | 200 | 1000 | 2000 | 3 | 30 | 150 | 1500 |
Alectinib M4 (metabolite) | |||||||||||
Binimetinib | |||||||||||
Cobimetinib | |||||||||||
Crizotinib | |||||||||||
Lorlatinib | |||||||||||
Osimertinib | |||||||||||
Dabrafenib | 5 | 25 | 50 | 250 | 500 | 2500 | 5000 | 7.5 | 75 | 375 | 3750 |
Imatinib | |||||||||||
Encorafenib |
Compound | Rt (min) | Parent Ion m/z | Fragment Ions m/z | Collision Energy (eV) |
---|---|---|---|---|
Alectinib | 2.7 | 483.3 | 381.1 | 36 |
396.1 | 23 | |||
Alectinib-D8 | 2.7 | 491.7 | 396.2 | 24 |
381.1 | 36 | |||
Alectinib M4 | 2.6 | 457.3 | 381 | 33 |
396 | 30 | |||
AZ5104 | 2.1 | 486.5 | 72.1 | 28 |
371.3 | 32 | |||
Binimetinib | 2.6 | 441.1 | 379.1 | 19 |
165 | 33 | |||
Bimetinib-13CD4 | 2.6 | 449.1 | 381 | 19 |
165 | 31 | |||
Cobimetinib | 2.8 | 532 | 84 | 29 |
249 | 30 | |||
Cobimetinib-13C6 | 2.8 | 538.1 | 84 | 29 |
255 | 32 | |||
Crizotinib | 2.2 | 450.1 | 177.1 | 38 |
260.2 | 23 | |||
Crizotinib-13C2D5 | 2.2 | 457.2 | 177.1 | 42 |
267.2 | 26 | |||
Dabrafenib | 3.2 | 520.1 | 307.2 | 33 |
343.2 | 26 | |||
Dabrafenib-D9 | 3.2 | 529.1 | 316.3 | 34 |
352.3 | 28 | |||
Encorafenib | 2.8 | 540.2 | 310.1 | 38 |
371.2 | 36 | |||
Encorafenib-13C2D3 | 2.8 | 544.2 | 310 | 34 |
371 | 37 | |||
Imatinib | 2.3 | 494.3 | 217.3 | 25 |
394.1 | 26 | |||
Imatinib-D8 | 2.3 | 502.4 | 225.1 | 26 |
394.1 | 27 | |||
Lorlatinib | 2.3 | 407.2 | 228.1 | 2 |
180.1 | 23 | |||
Osimertinib | 2.4 | 500.4 | 72.14 | 25 |
455.2 | 21 | |||
Osimertinib-13CD3 | 2.4 | 504.7 | 389.2 | 34 |
459.2 | 21 | |||
Trametinib | 3.1 | 616 | 226.2 | 46 |
254.2 | 37 | |||
Trametinib-13C6 | 3.1 | 622 | 232.2 | 48 |
260.2 | 39 |
Dabrafenib | Trametinib | Cobimetinib | Binimetinib | Encorafenib | Alectinib | Imatinib | Osimertinib | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Adults | Children | Adults | Children | Adults | Children | Adults | Children | Adults | Adults | Adults | Adults | |
Number of patients | 95 | 8 | 106 | 10 | 4 | 14 | 24 | 1 | 20 | 1 | 7 | 9 |
Average age (min–max) (years) | 58 [25–90] | 11 [3–16] | 62 [43–90] | 9 [1–17] | 55 [23–86] | 3.2 [0.1–13] | 62 [33–84] | 2 | 60 [33–83] | 66 | 60 [40–81] | 75.5 [45–86] |
Sex ratio | 1.2 | 1 | 2.3 | 2.3 | 3 | 1 | 1.6 | - | 0.6 | - | 1.3 | 0.3 |
Average dose (min–max) (mg/kg) | 4 [1.5–7.3] | 2 [0.4–4.7] | 0.028 [0.01–0.05] | 0.023 [0.01–0.05] | 0.5 [0.3–0.6] | 1.2 [0.9–2.7] | 1.2 [0.8–2.4] | 6.9 | 5.8 [3.8–12.2] | 21 | 4.5 [1.4–7.5] | 1.2 [0.6–2] |
Number of analyzed samples | 288 | 22 | 355 | 67 | 4 | 82 | 77 | 8 | 77 | 3 | 13 | 10 |
Molecules | LOD (ng/mL) (n = 6) | LOQ (ng/mL) (n = 6) | Linearity Range (ng/mL) (n = 6) | R2 | Accuracy (Bias, %) | Precision CV (%) | Recovery (n = 6) | Normalized Matrix Effect (NME) (n = 6) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Intra-Day (n = 6) | Inter-Day (n = 18) | Intra-Day (n = 6) | Inter-Day (n = 18) | QC2 | QC4 | QC2 | QC4 | |||||||||
Mean Value | CV (%) | Mean Value | CV (%) | Mean Value | CV (%) | Mean Value | CV (%) | |||||||||
Dabrafenib | 0.5 | 5 | 5–5000 | 0.9984 | 88.3–103.7 | 89–102.9 | 3.5–5.5 | 2.1–8.4 | 103.5 | 14.2 | 70.1 | 9.1 | 100 | 9.4 | 100 | 5.1 |
Trametinib | 0.5 | 1 | 1–200 | 0.9980 | 91.8–111.3 | 92.4–106.3 | 4.7–10.8 | 2–14.9 | 94.8 | 10.4 | 85.1 | 6.4 | 120 | 7.9 | 100 | 6.3 |
Cobimetinib | 0.4 | 2 | 2–2000 | 0.9986 | 88.3–103.1 | 89.6–102 | 4.7–7.3 | 2.5–4.9 | 97.8 | 5.8 | 113.8 | 7.1 | 120 | 3.2 | 100 | 5.5 |
Encorafenib | 1 | 5 | 5–5000 | 0.9990 | 90.8–106.3 | 92.8–103.2 | 3.9–7.4 | 5.2–14.8 | 88.3 | 15.1 | 114.9 | 8.8 | 110 | 10.8 | 100 | 9.9 |
Binimetinib | 0.2 | 2 | 2–2000 | 0.9989 | 89.5–103.1 | 92.7–99.5 | 3.4–6.7 | 2.5–8.4 | 110 | 11.1 | 107.7 | 10 | 100 | 8.6 | 100 | 6.5 |
Osimertinib | 2 | 2 | 2–2000 | 0.9959 | 96.9–113.7 | 100.3–109.8 | 4.3–8.1 | 5.6–7.9 | 106.1 | 10 | 98.3 | 12.5 | 100 | 7.5 | 120 | 12.8 |
AZ5104 | 0.1 | 0.2 | 0.2–200 | 0.9987 | 88.7–113.6 | 93.8–107.4 | 5.8–9.8 | 9.9–14.6 | 109.8 | 9 | 112.5 | 11.8 | 220 | 8.9 | 210 | 8.8 |
Crizotinib | 2 | 10 | 10–2000 | 0.9974 | 85.1–109 | 87.5–108.5 | 2.8–6.3 | 1–12.3 | 119.7 | 17.6 | 118.0 | 10.5 | 130 | 8.6 | 100 | 5.5 |
Alectinib | 0.2 | 2 | 2–2000 | 0.9984 | 85.4–103.9 | 89.8–102.4 | 5.3–8.8 | 1.9–14.4 | 106.4 | 12.1 | 113.1 | 13.8 | 70 | 6.7 | 70 | 10.9 |
Alectinib M4 | 0.2 | 2 | 2–2000 | 1 | 86.8–106.3 | 91.3–103.1 | 6.4–10.2 | 11.2–11.8 | 107.8 | 4 | 113.1 | 9.8 | 110 | 4.8 | 110 | 9.1 |
Imatinib | 2.5 | 5 | 5–5000 | 0.9990 | 88.7–97.5 | 92–94.9 | 3.9–5.9 | 6.1–11 | 109.3 | 6 | 111.6 | 9.2 | 120 | 3.3 | 110 | 6.7 |
Lorlatinib | 0.2 | 2 | 2–2000 | 0.9980 | 89.5–105.3 | 95.7–99 | 3.7–6.9 | 8–14.6 | 104.6 | 8.1 | 114.2 | 14.5 | 80 | 5.3 | 110 | 15.1 |
Compound | Measured Value (µg/L) | Mean (µg/L) | Z-Score |
---|---|---|---|
Alectinib | 296 | 316 | −0.27 |
Binimetinib | 150 | 137 | 0.64 |
Cobimetinib | 74 | 64.6 | 1.12 |
Crizotinib | 78 | 72.8 | 1.3 |
Dabrafenib | 58 | 53.1 | 1.1 |
Encorafenib | 50 | 44.1 | 0.94 |
Imatinib | 528 | 446 | 1.38 |
Trametinib | 5.5 | 4.74 | 0.98 |
Dabrafenib | Trametinib | Cobimetinib | Binimetinib | Encorafenib | Alectinib | Alectinib M4 | Imatinib | Osimertinib | AZ5104 | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Adults (n = 288) | Children (n = 22) | Adults (n = 355) | Children (n = 67) | Adults (n = 4) | Children (n = 82) | Adults (n = 92) | Children (n = 8) | Adults (n = 77) | Adults (n = 3) | Adults (n = 3) | Adults (n = 13) | Adults (n = 10) | Adults (n = 10) | |
Concentration range CI 95% (ng/mL) | [88–122] | [26–178] | [11–13] | [11–14] | [24–94] | [74–118] | [51–64] | [37–204] | [16–21] | [292–424] | [125–170] | [1132–1702] | [122–320] | [16–56] |
IQR (ng/mL) | [29–114] | [15–131] | [8–14] | [6.5–17] | [46.5–83] | [34–114] | [38–69] | [62–143] | [10–22] | [302–408] | [132–168] | [1254–1742] | [95–321] | [11–47] |
Median concentration (ng/mL) | 53.5 | 18.4 | 11 | 9.7 | 70 | 64.3 | 52 | 100 | 15 | 346 | 156 | 1618 | 207 | 25 |
Mean concentration (ng/mL) | 105.3 | 102.3 | 12.4 | 12.6 | 59.3 | 96.3 | 57.4 | 120 | 18.6 | 358 | 147 | 1417 | 221 | 32 |
Dose–weight-adjusted median concentration (ng/mL/mg/kg) | 14 | 19.1 | 386.3 | 538.5 | 138.1 | 62.6 | 41.6 | 14.6 | 2.6 | 16.7 | 7.5 | 321.7 | 211.4 | 21.7 |
Dose–weight-adjusted mean concentration (ng/mL/mg/kg) | 28.3 | 62.3 | 443.8 | 578.4 | 145.7 | 85.4 | 48.8 | 17.5 | 3.4 | 17.3 | 7.1 | 363.6 | 196.7 | 25.8 |
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Bellouard, M.; Donadieu, J.; Thiebot, P.; Giroux Leprieur, E.; Saiag, P.; Etting, I.; Dugues, P.; Abe, E.; Alvarez, J.-C.; Larabi, I.-A. Validation of Liquid Chromatography Coupled with Tandem Mass Spectrometry for the Determination of 12 Tyrosine Kinase Inhibitors (TKIs) and Their Application to Therapeutic Drug Monitoring in Adult and Pediatric Populations. Pharmaceutics 2024, 16, 5. https://doi.org/10.3390/pharmaceutics16010005
Bellouard M, Donadieu J, Thiebot P, Giroux Leprieur E, Saiag P, Etting I, Dugues P, Abe E, Alvarez J-C, Larabi I-A. Validation of Liquid Chromatography Coupled with Tandem Mass Spectrometry for the Determination of 12 Tyrosine Kinase Inhibitors (TKIs) and Their Application to Therapeutic Drug Monitoring in Adult and Pediatric Populations. Pharmaceutics. 2024; 16(1):5. https://doi.org/10.3390/pharmaceutics16010005
Chicago/Turabian StyleBellouard, Marie, Jean Donadieu, Pauline Thiebot, Etienne Giroux Leprieur, Philippe Saiag, Isabelle Etting, Pamela Dugues, Emuri Abe, Jean-Claude Alvarez, and Islam-Amine Larabi. 2024. "Validation of Liquid Chromatography Coupled with Tandem Mass Spectrometry for the Determination of 12 Tyrosine Kinase Inhibitors (TKIs) and Their Application to Therapeutic Drug Monitoring in Adult and Pediatric Populations" Pharmaceutics 16, no. 1: 5. https://doi.org/10.3390/pharmaceutics16010005