Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Data Collection
2.2. Dosing, Pharmacokinetic Sampling and Quantification
2.3. Genotyping
2.4. PopPK Analysis
2.5. Covariate Model
2.6. Model Evaluation
3. Results
3.1. Patients and Data
3.2. Base Model
3.3. Covariate Model
3.4. Model Evaluation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patient Characteristics (n = 37) | Median [IQR] or n (%) |
---|---|
Age [years] | 60 [53.5–65.5] |
Sex [female/male] | 19 (51.4)/18 (48.6) |
Weight [kg] | 75 [64.05–88.25] |
Height [cm] | 174 [168–181] |
BSA [m2] | 1.84 [1.75–2.07] |
Diagnosis | |
PMF | 18 (48.7) |
Post-ET MF | 9 (24.3) |
Post-PV MF | 10 (27) |
Dosing regime | |
Q6H | 30 (81) |
Q24H | 7 (19) |
DIPSS/MYSEC | |
Intermediate-1 | 2 (5)/1 (3) |
Intermediate-2 | 15 (40)/14 (38) |
High Risk | 1 (3)/4 (11) |
Mutation | |
JAK2 | 26 (70.3) |
CALR | 7 (18.9) |
MPL | 1 (3) |
TET2 | 9 (24.3) |
ASXL1 | 13 (35.1) |
Blood chemistry, serum levels | |
AST [U/L] | 21 [15.5–31.5] |
ALT [U/L] | 21 [18.5–47.5] |
De Ritis Ratio | 0.76 [0.58–1.07] |
Albumin [g/L] | 37.8 [34.6–41.4] |
Alkaline Phosphatase [U/L] | 85 [63–115] |
Bilirubin [mg/dL] | 0.6 [0.5–0.8] |
Fibroscan [kPa] | 5.6 [4.8–7] |
Missing Data | 14 (37.8) |
GSTA1 52G > A | 28 (75.7) |
GSTM1 Deletion | 19 (51.35) |
Mucositis Grade 1/2/3/4 | 10 (27)/14 (38)/1 (2.7)/1 (2.7) |
aGvHD Grade 1/2/3 | 10 (27)/7 (19)/4 (11) |
cGvHD Grade 1/2/3 | 12 (32)/6 (16)/1 (2.7) |
SOS | 2 (5.4) |
Relapse | 2 (5.4) |
Death | 5 (13.5) |
Parameters | Final Model | SIR (M/m = 5000/1000) | ||
---|---|---|---|---|
Estimate | RSE (%) | Shrinkage (%) | 95% CI | |
CLBu [L/h] | 16.3 | 3.6 | - | 15.18–17.35 |
VBu [L] | 61.5 | 2 | - | 59.37–63.78 |
CLSu [L/h] | 1.61 | 37 | - | 0.84–2.24 |
VSu [L] | 48.8 | 35.2 | - | 30.75–78.46 |
MF | 0.0704 | 28.6 | - | 0.0463–0.1029 |
COV_VBu_TBW [kg] | 0.854 | 11.6 | - | 0.665–1.059 |
COV_CLSu_GSTA1 | 1.43 | 43.6 | - | 0.63–2.40 |
IIV CLBu [CV%] | 21.5 | 14.8 | 2 | 16.4–27.4 |
IIV VBu [CV%] | 10 | 12 | 18 | 7.2–12.1 |
IIV CLSu [CV%] | 112.8 | 26.1 | 22 | 80.3–206.2 |
IIV VSu [CV%] | 77.6 | 14.2 | 18 | 59.2–106.4 |
IOV CLBu [CV%] | 7.6 | 13.5 | 39 | 5.6–9.1 |
Prop. σBu [CV%] | 7.1 | 12.8 | 14 | 6.3–8.2 |
Prop. σSu [CV%] | 36.2 | 7.2 | 12 | 32.6–40.1 |
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Dadkhah, A.; Wicha, S.G.; Kröger, N.; Müller, A.; Pfaffendorf, C.; Riedner, M.; Badbaran, A.; Fehse, B.; Langebrake, C. Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation. Pharmaceutics 2022, 14, 1145. https://doi.org/10.3390/pharmaceutics14061145
Dadkhah A, Wicha SG, Kröger N, Müller A, Pfaffendorf C, Riedner M, Badbaran A, Fehse B, Langebrake C. Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation. Pharmaceutics. 2022; 14(6):1145. https://doi.org/10.3390/pharmaceutics14061145
Chicago/Turabian StyleDadkhah, Adrin, Sebastian Georg Wicha, Nicolaus Kröger, Alexander Müller, Christoph Pfaffendorf, Maria Riedner, Anita Badbaran, Boris Fehse, and Claudia Langebrake. 2022. "Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation" Pharmaceutics 14, no. 6: 1145. https://doi.org/10.3390/pharmaceutics14061145
APA StyleDadkhah, A., Wicha, S. G., Kröger, N., Müller, A., Pfaffendorf, C., Riedner, M., Badbaran, A., Fehse, B., & Langebrake, C. (2022). Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation. Pharmaceutics, 14(6), 1145. https://doi.org/10.3390/pharmaceutics14061145