Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment
Abstract
:1. Introduction
2. Results
2.1. Method Development
2.1.1. Optimization of the Sample Preparation Procedure
2.1.2. Optimization of the Chromatographic Conditions
2.1.3. Optimization of the Detection Conditions
2.2. Method Validation
2.2.1. Selectivity
2.2.2. Carry-Over
2.2.3. Matrix Effect
2.2.4. Stability
2.2.5. Linearity and Calibration Range
2.2.6. Precision and Accuracy
2.3. Method Application
2.3.1. Clinical Application to Therapeutic Drug Monitoring
2.3.2. Application to Clinical Pharmacokinetic Evaluation
3. Materials and Methods
3.1. Chemicals and Reagents
3.2. Stock and Working Solutions
3.3. Blank and Patient Plasma
3.4. Sample Preparation Procedure
3.5. Instruments and Software
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Analyte | RIB | ABE | PAL | ANA | LET | FUL |
---|---|---|---|---|---|---|
LOD 1 DAD | 30 | 40 | 120 | 1600 | 140 | 6190 |
LOD FLD | ND | ND | ND | 900 | 220 | 600 |
LOD MS | 20 | 8 | 1 | <0.5 2 | 1 | 1.5 |
Expected literature range Cmin–Cmax | 711–3500 [24] | 102.65–1381 [25] | 72.8–185.5 [26] | 22–52.6 [27] | 28.4–349.2 [28] | 16–25 [29] |
Analyte | tR (min) | CE (eV) | m/z Transition |
---|---|---|---|
RIB | 5.4 | 10 | 435.27 → 322.14 |
ABE | 5.5 | 10 | 507.30 → 393.16 |
PAL | 6.2 | 30 | 448.25 → 380.18 |
ANA | 8.2 | 20 | 294.20 → 225.14 |
LET | 8.5 | 10 | 286.13 → 217.08 |
FUL | 9.9 | 20 | 607.38 → 467.20 |
Analyte | Concentration (ng/mL) | Matrix Effect (%) | CV (%) | Analyte | Concentration (ng/mL) | Matrix Effect (%) | CV (%) |
---|---|---|---|---|---|---|---|
RIB | 62.5 | 108.34 | 3.15 | ANA | 2.5 | 90.36 | 6.85 |
2500 | 102.26 | 2.14 | 100 | 106.78 | 3.69 | ||
ABE | 37.5 | 77.80 | 6.69 | LET | 6.25 | 83.81 | 9.94 |
1500 | 73.10 | 2.47 | 250 | 101.67 | 6.97 | ||
PAL | 6.25 | 115.74 | 5.70 | FUL | 12.5 | 92.78 | 8.92 |
250 | 106.74 | 4.08 | 500 | 101.08 | 6.90 |
Analyte | Concentration (ng/mL) | Bench Top (2 h, 25 °C) | Auto- Sampler (10 h, 10 °C) | 1 FT Cycle (30 min, −18–25 °C) | 2 FT Cycles (30 min, −18–25 °C) | 3 FT Cycles (30 min, −18–25 °C) | Long-Term (2 Weeks, −18 °C) | |
---|---|---|---|---|---|---|---|---|
RIB | 62.5 | Bias (%) | 6.01 | 8.95 | 7.88 | 1.69 | 6.00 | 13.89 |
CV (%) | 5.07 | 9.50 | 12.89 | 11.16 | 5.02 | 14.77 | ||
2500 | Bias (%) | 4.96 | −6.47 | 11.10 | −1.66 | −4.69 | −10.69 | |
CV (%) | 1.69 | 5.18 | 7.05 | 7.05 | 1.61 | 4.45 | ||
ABE | 37.5 | Bias (%) | 9.09 | 11.51 | 13.23 | −7.43 | 14.07 | 7.60 |
CV (%) | 8.04 | 7.41 | 3.47 | 6.89 | 2.55 | 7.84 | ||
1500 | Bias (%) | −0.10 | 14.88 | 9.37 | 5.68 | 1.13 | 3.09 | |
CV (%) | 3.82 | 4.25 | 1.56 | 1.56 | 6.93 | 5.21 | ||
PAL | 6.2 | Bias (%) | 3.08 | 13.69 | 14.97 | 1.86 | 2.81 | 12.29 |
CV (%) | 10.27 | 1.35 | 4.99 | 6.62 | 4.84 | 9.95 | ||
250 | Bias (%) | −4.37 | 14.95 | 6.35 | −1.65 | −7.90 | −3.08 | |
CV (%) | 3.35 | 5.32 | 5.95 | 5.95 | 3.84 | 10.44 | ||
ANA | 2.5 | Bias (%) | −10.33 | 2.27 | −7.88 | −2.80 | −3.98 | 3.09 |
CV (%) | 5.01 | 11.15 | 1.93 | 4.74 | 5.32 | 3.87 | ||
100 | Bias (%) | −0.62 | 4.89 | 6.65 | 8.39 | −0.69 | −0.40 | |
CV (%) | 2.13 | 2.60 | 2.78 | 2.78 | 6.48 | 8.54 | ||
LET | 6.25 | Bias (%) | −6.81 | 6.11 | −0.06 | −6.52 | −3.50 | −10.44 |
CV (%) | 8.64 | 7.01 | 14.71 | 5.53 | 6.79 | 2.90 | ||
250 | Bias (%) | 6.16 | −0.29 | 2.07 | −0.26 | −7.61 | −7.75 | |
CV (%) | 1.66 | 2.95 | 2.80 | 2.80 | 9.51 | 8.45 | ||
FUL | 12.5 | Bias (%) | −9.36 | 7.38 | −14.59 | −13.24 | −8.90 | −5.01 |
CV (%) | 14.83 | −3.68 | 10.68 | 14.99 | 4.62 | 9.00 | ||
500 | Bias (%) | 2.32 | −8.06 | 2.23 | 4.49 | −7.51 | −1.62 | |
CV (%) | 1.74 | 1.37 | 8.71 | 8.71 | 7.33 | 4.46 |
Analyte | RIB | ABE | PAL | ANA | LET | FUL | |
---|---|---|---|---|---|---|---|
Range (ng/mL) | 25–5000 | 15–3000 | 3.1–500 | 1–200 | 2.5–500 | 5–1000 | |
Within-day 1 | Slope | 84.48 | 500.67 | 6194.67 | 27,818.67 | 1235.33 | 664.97 |
CV (%) | 3.94 | 2.00 | 5.68 | 4.77 | 4.93 | 4.97 | |
Intercept | 875.13 | −246.27 | −2113.33 | 1840.33 | 356.07 | 452.73 | |
Between-day 2 | Slope | 78.44 | 459.75 | 5940.75 | 25,972.75 | 1350.25 | 513.63 |
CV (%) | 7.52 | 40.23 | 10.49 | 15.52 | 9.75 | 27.09 | |
Intercept | 771.03 | 2342.95 | −3629.25 | 8426.75 | 576.38 | 627.63 | |
R | 0.9941–0.9985 | 0.9955–0.9983 | 0.9950–0.9991 | 0.9958–0.9990 | 0.9931–0.9996 | 0.9953–0.9984 |
Intra-Day | Inter-Day | ||||
---|---|---|---|---|---|
Analyte | Concentration (ng/mL) | Bias (%) | CV (%) | Bias (%) | CV (%) |
RIB | 25 | −1.8 | 11.5 | −14.7 | 19.9 |
50 | 6.4 | 8.9 | 7.0 | 11.7 | |
2000 | 8.5 | 3.7 | −0.1 | 7.9 | |
3750 | −1.5 | 3.7 | −7.2 | 8.0 | |
ABE | 15 | 4.2 | 19.4 | −7.8 | 17.4 |
30 | 2.2 | 14.8 | −6.8 | 4.1 | |
1200 | 12.3 | 14.6 | 4.4 | 3.2 | |
2250 | 14.9 | 3.1 | −12.9 | 5.0 | |
PAL | 3.1 | 15.4 | 7.1 | 9.5 | 7.9 |
6.2 | 10.3 | 6.4 | 9.2 | 8.9 | |
250 | 15.0 | 4.6 | 3.1 | 5.1 | |
468.8 | 11.1 | 6.0 | −0.3 | 4.3 | |
ANA | 1 | 8.3 | 3.7 | −0.5 | 6.1 |
2 | 4.6 | 9.6 | 3.3 | 6.0 | |
80 | 0.1 | 14.3 | −5.4 | 3.9 | |
150 | 5.4 | 6.2 | −3.7 | 1.6 | |
LET | 2.5 | 14.5 | 3.7 | −14.8 | 16.4 |
5 | 5.8 | 11.5 | 14.6 | 6.9 | |
200 | 6.8 | 7.1 | 4.0 | 7.9 | |
375 | 4.2 | 5.1 | −4.9 | 6.0 | |
FUL | 5 | 3.3 | 16.2 | −2.7 | 11.9 |
10 | 11.6 | 14.9 | −14.3 | 13.9 | |
400 | 4.6 | 15.0 | −6.3 | 5.4 | |
750 | −1.1 | 7.2 | 2.2 | 14.9 |
Patient | Sampling Day 1 | CDK4/6 Inhibitor | Plasma Concentration (ng/mL) | Endocrine Agent | Plasma Concentration (ng/mL) |
---|---|---|---|---|---|
1 | NA | ABE (300 mg daily) | 425.79 | LET (2.5 mg daily) | 109.99 |
2 | day 24 | RIB (600 mg daily) | 57.43 | LET (2.5 mg daily) | 141.11 |
3 | day 16 | RIB (600 mg daily) | 682.16 | LET (2.5 mg daily) | 146.21 |
4 | day 1 | RIB (600 mg daily) | 1519.81 | LET (2.5 mg daily) | 139.46 |
5 | day 12 | RIB (600 mg daily) | 1192.77 | ANA (1 mg daily) | 43.96 |
6 | day 28 | RIB (600 mg daily) | 27.18 | EXE (25 mg daily) | ND |
7 | day 27 | RIB (600 mg daily) | 40.67 | FUL (500 mg monthly) | 20.73 |
8 | day 27 | PAL (125 mg daily) | 7.55 | FUL (500 mg monthly) | 22.69 |
9 | day 28 | PAL (125 mg daily) | <LOQ | FUL (500 mg monthly) | 22.13 |
10 | day 23 | PAL (125 mg daily) | <LOD | FUL (500 mg monthly) | 24.56 |
RIB | ABE | PAL | ANA | LET | FUL | |
---|---|---|---|---|---|---|
1 | 25 | 15 | 2.5 | 1 | 2.5 | 5 |
2 | 50 | 30 | 5 | 2 | 5 | 10 |
3 | 125 | 75 | 12.5 | 5 | 12.5 | 25 |
4 | 250 | 150 | 25 | 10 | 25 | 50 |
5 | 750 | 450 | 75 | 30 | 75 | 150 |
6 | 1500 | 900 | 150 | 60 | 150 | 300 |
7 | 2500 | 1500 | 250 | 100 | 250 | 500 |
8 | 3750 | 2250 | 375 | 150 | 375 | 750 |
9 | 5000 | 3000 | 500 | 200 | 500 | 1000 |
t (min) | % B | Flow Rate (mL/min) |
---|---|---|
0 | 15 | 0.4 |
8.5 | 100 | 0.4 |
10 | 100 | 0.4 |
10.5 | 15 | 0.4 |
11.3 | 100 | 1 |
13 | 100 | 1 |
13.2 | 15 | 1 |
13.5 | 15 | 0.4 |
18 | 15 | 0.4 |
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Turković, L.; Bočkor, L.; Ekpenyong, O.; Silovski, T.; Lovrić, M.; Crnković, S.; Nigović, B.; Sertić, M. Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment. Pharmaceuticals 2022, 15, 614. https://doi.org/10.3390/ph15050614
Turković L, Bočkor L, Ekpenyong O, Silovski T, Lovrić M, Crnković S, Nigović B, Sertić M. Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment. Pharmaceuticals. 2022; 15(5):614. https://doi.org/10.3390/ph15050614
Chicago/Turabian StyleTurković, Lu, Luka Bočkor, Oscar Ekpenyong, Tajana Silovski, Mila Lovrić, Slaven Crnković, Biljana Nigović, and Miranda Sertić. 2022. "Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment" Pharmaceuticals 15, no. 5: 614. https://doi.org/10.3390/ph15050614
APA StyleTurković, L., Bočkor, L., Ekpenyong, O., Silovski, T., Lovrić, M., Crnković, S., Nigović, B., & Sertić, M. (2022). Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment. Pharmaceuticals, 15(5), 614. https://doi.org/10.3390/ph15050614