Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Subjects
2.3. Sampling
2.4. Determination of Clinical Biochemistry Parameters
2.5. Determination of Genotypes
2.5.1. Identification of CYP2C9*3 and *13 Alleles
2.5.2. Identification of SLCO1B1 388A>G and 521T>C
2.6. Determination of Serum Torsemide Concentration
2.7. PK Analysis
2.8. Model Development
2.8.1. Establishment of Structural Base Model
2.8.2. Covariate Analysis
2.9. Model Evaluation
2.10. Model Reconfirmation
3. Results and Discussion
3.1. Study Design and Demographic Analysis
3.2. Genetic Polymorphism Analysis
3.3. Determination of Torsemide Serum Concentrations
3.4. PK Results by NCA
3.5. Pop-PK Model Analysis
3.6. Pop-PK Model Interpretation
3.7. Pop-PK Model Evaluation
3.8. Reconfirmation of Torsemide Pop-PK Model
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
PK | Pharmacokinetic |
Pop-PK | Population pharmacokinetic |
CrCl | Creatinine clearance |
BSA | Body surface area |
BMI | Body mass index |
ALP | Alkaline phosphatase |
AST | Aspartate transaminase |
ALT | Alanine transaminase |
GFR | Glomerular filtration rate |
BUN | Blood urea nitrogen |
HPLC | High-performance liquid chromatography |
UV | Ultraviolet |
HPLC-UV | High-performance liquid chromatography-ultraviolet |
PCR-RFLP | Polymerase chain reaction–restriction fragment length polymorphism |
SD | Standard deviation |
ANOVA | Analysis of variance |
tv | Typical value |
NCA | Non-compartment analysis |
AIC | Akaike’s information criterion |
AUC | Area under the curve |
IIV | Inter-individual variability |
OFV | Objective function value |
SE | Standard error |
RSE | Relative standard error |
VPC | Visual predictive check |
NPDE | Normalized prediction distribution error |
FOCE | First-order conditional estimates |
NLME | Nonlinear mixed-effects |
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CYP2C9 | |||||||
---|---|---|---|---|---|---|---|
Genotype | *1*1 | *1*3 | *1*13 | ||||
Subject No | 97 (86.61%) | 12 (10.71%) | 3 (2.68%) | ||||
Phenotype | EM | IM | IM | ||||
OATP1B1 | |||||||
Genotype | *1a*1a | *1a*1b | *1b*1b | *1a*15 | *1b*15 | *15*15 | |
Subject No | 11 (9.82%) | 38 (33.93%) | 37 (33.04%) | 4 (3.57%) | 19 (16.96%) | 3 (2.68%) | |
Phenotype | ET | ET | ET | IT | IT | PT | |
OATP1B1/CYP2C9 | |||||||
Genotype | OATP1B1 | *1a*1a, *1a*1b, *1b*1b | *1a*1a, *1a*1b, *1b*1b | *1a*15, *1b*15 | *1a*15, *1b*15 | *15*15 | *15*15 |
CYP2C9 | *1*1 | *1*3, *1*13 | *1*1 | *1*3, *1*13 | *1*1 | *1*3, *1*13 | |
Subject No | 80 (71.43%) | 6 (5.36%) | 17 (15.18%) | 6 (5.36%) | 0 (0%) | 3 (2.68%) | |
Phenotype | ET/EM | ET/IM | IT/EM | IT/IM | PT/EM | PT/IM |
Model | Description | nParameter | −2LL | AIC | △−2LL | △AIC | Compared with |
---|---|---|---|---|---|---|---|
Compartment model | |||||||
01 | 1-compartment | 7 | −1106.512 | −1092.512 | - | - | - |
02 * | 2-compartment | 11 | −2201.649 | −2179.649 | −1095.14 | −1087.14 | 01 |
Absorption model | |||||||
02 | No Tlag | 11 | −2201.649 | −2179.649 | - | - | - |
03 * | With Tlag | 13 | −2757.066 | −2731.066 | −555.42 | −551.42 | 02 |
Residual error model | |||||||
03 * | Proportional | 13 | −2757.066 | −2731.066 | - | - | - |
04 | Additive | 13 | 363.99 | 389.99 | 3121.06 | 3121.06 | 03 |
05 | Log additive | 13 | −11.59 | 14.41 | 2745.48 | 2745.48 | 03 |
06 | Mixed | 14 | −2529.50 | −2501.50 | 227.57 | 229.57 | 03 |
07 | Power | 13 | 528.70 | 554.70 | 3285.77 | 3285.77 | 03 |
IIV model | |||||||
08 * | Remove IIV on Ka | 12 | −2765.86 | −2741.86 | −8.80 | −10.80 | 03 |
09 | Remove IIV on V/F | 12 | −2530.69 | −2506.69 | 226.37 | 224.37 | 03 |
10 | Remove IIV on V2/F | 12 | −2705.07 | −2643.98 | 52.00 | 87.09 | 03 |
11 | Remove IIV on CL/F | 12 | −1834.89 | −1810.89 | 922.18 | 920.18 | 03 |
12 | Remove IIV on CL2/F | 12 | −2729.3692 | −2705.3692 | 27.70 | 25.70 | 03 |
13 | Remove IIV on Tlag | 12 | −2477.5333 | −2453.5333 | 279.53 | 277.53 | 03 |
Model | Description | Summary | OFV | △OFV | Compared with | nParameter |
---|---|---|---|---|---|---|
1 | Base model | - | −2765.86 | - | - | 12 |
Forward addition | ||||||
2 | OATP1B1 on V/F | - | −2775.354 | −9.490 | Base model | 14 |
3 | OATP1B1 on V2/F | - | −2766.150 | −0.286 | Base model | 14 |
4 | OATP1B1 on CL/F | - | −2772.458 | −6.594 | Base model | 14 |
5 | OATP1B1 on CL2/F | - | −2778.904 | −13.040 | Base model | 14 |
6 | OATP1B1 on Tlag | - | −2765.983 | −0.119 | Base model | 14 |
7 | CYP2C9 on V/F | - | −2767.611 | −1.747 | Base model | 13 |
8 | CYP2C9 on V2/F | - | −2768.067 | −2.203 | Base model | 13 |
9 | CYP2C9 on CL/F | - | −2813.517 | −47.652 | Base model | 13 |
10 | CYP2C9 on CL2/F | - | −2781.570 | −15.706 | Base model | 13 |
11 | CYP2C9 on Tlag | - | −2765.885 | −0.021 | Base model | 13 |
12 | OATP1B1 on V/F, CL/F | - | −2782.070 | −6.716 | Model 2 | 16 |
13 | OATP1B1 on V/F, CL/F, CL2/F | - | −2797.111 | −15.041 | Model 12 | 18 |
14 | OATP1B1 on V/F, CL/F, CL2/F CYP2C9 on CL/F | - | −2838.7158 | −41.605 | Model 13 | 19 |
15 | OATP1B1 on V/F, CL/F, CL2/F CYP2C9 on CL/F, CL2/F | Full model | −2850.9748 | −12.259 | Model 14 | 20 |
Backward removal | ||||||
16 | OATP1B1 on V/F, CL/F, CL2/F CYP2C9 on CL2/F | Full model deleted CYP2C9 on CL/F | −2779.106 | 71.8688 | Model 15 | 19 |
17 | OATP1B1 on V/F, CL/F, CL2/F CYP2C9 on CL/F | Full model deleted CYP2C9 on CL2/F | −2837.9679 | 13.0069 | Model 15 | 19 |
18 | OATP1B1 on V/F, CL/F CYP2C9 on CL/F, CL2/F | Full model deleted OATP1B1 on CL2/F | −2844.7793 | 6.1955 | Model 15 | 18 |
19 | OATP1B1 on V/F, CL2/F CYP2C9 on CL/F, CL2/F | Full model deleted OATP1B1 on CL/F | −2850.8641 | 0.1107 | Model 15 | 18 |
20 | OATP1B1 on CL/F, CL2/F CYP2C9 on CL/F, CL2/F | Full model deleted OATP1B1 on V/F | −2841.5173 | 9.4575 | Model 15 | 18 |
21 * | OATP1B1 on V/F CYP2C9 on CL/F, CL2/F | Full model deleted OATP1B1 on CL/F, CL2/F | −2844.404 | 6.5708 | Model 15 | 16 |
Parameter | Estimate | SE | RSE (%) | Shrinkage (%) | IIV (%) |
---|---|---|---|---|---|
Final model | |||||
tvV/F (L) | 1.027 | 0.081 | 7.92 | - | - |
tvCL/F (L/h) | 1.740 | 0.073 | 4.19 | - | - |
tvV2/F (L) | 3.914 | 0.104 | 2.65 | - | - |
tvCL2/F (L/h) | 0.828 | 0.056 | 6.71 | - | - |
tvKa (1/h) | 0.861 | 0.025 | 2.93 | - | - |
tvTlag (h) | 0.274 | 0.018 | 6.64 | - | - |
dV/FdOATP1B1IT | −0.410 | 0.129 | 31.54 | - | - |
dV/FdOATP1B1PT | −0.646 | 0.204 | 31.56 | - | - |
dCL/FdCYP2C9EM | 0.510 | 0.063 | 12.37 | - | - |
dCL2/FdCYP2C9EM | 0.365 | 0.056 | 15.23 | - | - |
ω2v/F | 0.562 | 0.070 | 12.45 | 21.040 | 74.949 |
ω2CL/F | 0.029 | 0.004 | 13.34 | 2.790 | 17.098 |
ω2V2/F | 0.036 | 0.007 | 20.74 | 23.780 | 18.938 |
ω2CL2/F | 0.022 | 0.006 | 25.28 | 38.530 | 14.899 |
ω2Tlag | 0.341 | 0.079 | 23.16 | 23.370 | 58.367 |
ε | 0.136 | 0.010 | 7.15 | - | - |
Parameter | Final Model | Bootstrap (n = 1000) | ||
---|---|---|---|---|
Estimate | 95% CI | Median | 95% CI | |
tvV/F (L) | 1.027 | 0.868–1.187 | 1.042 | 0.861–1.233 |
tvCL/F (L/h) | 1.740 | 1.597–1.884 | 1.733 | 1.473–2.005 |
tvV2/F (L) | 3.914 | 3.710–4.118 | 3.892 | 3.698–4.131 |
tvCL2/F (L/h) | 0.828 | 0.719–0.937 | 0.826 | 0.667–1.102 |
tvKa (1/h) | 0.861 | 0.811–0.910 | 0.859 | 0.818–0.919 |
tvTlag (h) | 0.274 | 0.238–0.309 | 0.278 | 0.226–0.324 |
dV/FdOATP1B1IT | −0.410 | −0.663–−0.156 | −0.409 | −0.586–−0.203 |
dV/FdOATP1B1PT | −0.646 | −1.046–−0.246 | −0.664 | −1.000–−0.096 |
dCL/FdCYP2C9EM | 0.510 | 0.386–0.634 | 0.505 | 0.310–0.786 |
dCL2/FdCYP2C9EM | 0.365 | 0.256–0.473 | 0.357 | 0.093–0.659 |
ω2v/F | 0.562 | 0.425–0.699 | 0.536 | 0.357–0.715 |
ω2CL/F | 0.029 | 0.022–0.037 | 0.028 | 0.021–0.035 |
ω2V2/F | 0.036 | 0.021–0.050 | 0.035 | 0.016–0.053 |
ω2CL2/F | 0.022 | 0.011–0.033 | 0.019 | 0.002–0.036 |
ω2Tlag | 0.341 | 0.186–0.495 | 0.356 | 0.089–0.623 |
ε | 0.136 | 0.117–0.156 | 0.137 | 0.117–0.150 |
Parameter | Estimate * | NONMEM−NLME Difference (%) of Estimate | RSE (%) * | NONMEM−NLME Difference of RSE | IIV (%) * | NONMEM−NLME Difference of IIV |
---|---|---|---|---|---|---|
Final model | ||||||
tvV/F (L) | 1.027 | 0.00 | 8.04 | 0.12 | - | - |
tvCL/F (L/h) | 1.740 | 0.00 | 4.32 | 0.13 | - | - |
tvV2/F (L) | 3.914 | 0.00 | 2.68 | 0.03 | - | - |
tvCL2/F (L/h) | 0.828 | 0.00 | 6.80 | 0.09 | - | - |
tvKa (1/h) | 0.861 | 0.00 | 2.94 | 0.01 | - | - |
tvTlag (h) | 0.274 | 0.00 | 6.66 | 0.02 | - | - |
dV/FdOATP1B1IT | −0.410 | 0.00 | 31.54 | 0.00 | - | - |
dV/FdOATP1B1PT | −0.646 | 0.00 | 31.59 | 0.03 | - | - |
dCL/FdCYP2C9EM | 0.510 | 0.00 | 12.39 | 0.02 | - | - |
dCL2/FdCYP2C9EM | 0.365 | 0.00 | 15.29 | 0.06 | - | - |
ω2V/F | 0.562 | 0.00 | 12.47 | 0.02 | 74.967 | 0.02 |
ω2CL/F | 0.029 | 0.00 | 13.38 | 0.04 | 17.029 | −0.07 |
ω2V2/F | 0.036 | 0.00 | 20.78 | 0.04 | 18.974 | 0.04 |
ω2CL2/F | 0.022 | 0.00 | 25.91 | 0.63 | 14.832 | −0.07 |
ω2Tlag | 0.341 | 0.00 | 23.17 | 0.01 | 58.395 | 0.03 |
ε | 0.136 | 0.00 | 7.15 | 0.00 | - | - |
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Jeong, S.-H.; Jang, J.-H.; Cho, H.-Y.; Lee, Y.-B. Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms. Pharmaceutics 2022, 14, 771. https://doi.org/10.3390/pharmaceutics14040771
Jeong S-H, Jang J-H, Cho H-Y, Lee Y-B. Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms. Pharmaceutics. 2022; 14(4):771. https://doi.org/10.3390/pharmaceutics14040771
Chicago/Turabian StyleJeong, Seung-Hyun, Ji-Hun Jang, Hea-Young Cho, and Yong-Bok Lee. 2022. "Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms" Pharmaceutics 14, no. 4: 771. https://doi.org/10.3390/pharmaceutics14040771
APA StyleJeong, S.-H., Jang, J.-H., Cho, H.-Y., & Lee, Y.-B. (2022). Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms. Pharmaceutics, 14(4), 771. https://doi.org/10.3390/pharmaceutics14040771