Pharmacokinetic–Pharmacodynamic Model for the Testosterone-Suppressive Effect of Leuprolide in Normal and Prostate Cancer Rats
Abstract
:1. Introduction
2. Results
2.1. In Vitro Release Evaluation of Sustained Release (SR) Depot
2.2. Pharmacokinetic Evaluation of Leuprolide
2.3. Pharmacodynamic Evaluation for the Testosterone-Suppressive Effect
2.4. Pharmacokinetic–Pharmacodynamic (PK-PD) Modeling of Testosterone-Suppressive Effect of Leuprolide
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. In Vitro Release Test of SR Depot
4.3. Animals and Experimental Design
4.4. Measurement of Leuprolide in Plasma Samples
4.5. Measurement of Testosterone in Plasma Samples
4.6. Estimation of PK, PD Parameters and Data Analysis
4.7. Development and Evaluation of PK–PD Model of Leuprolide
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Not available. |
Parameters | IV (Group 1) | SC (Group 3) |
---|---|---|
k (h−1) | 1.42 ± 0.24 | 1.06 ± 0.55 |
ka (h−1) | - | 16.67 ± 2.55 |
CL (mL/h) | 248.61 ± 35.07 | 514.46 ± 40.10 |
Vd (mL) | 192.95 ± 54.24 | 487.40 ± 29.02 |
Cmax (ng/mL) | 97.10 ± 13.04 a | 41.53 ± 4.61 |
t1/2 (h) | 0.52 ± 0.10 | 0.66 ± 0.03 |
AUC0-t (h·ng/mL) | 103.44 ± 16.93 | 51.20 ± 9.56 |
AUC0–∞ (h·ng/mL) | 105.50 ± 17.27 | 53.33 ± 9.96 |
F (%) | 100 | 50.6 |
Parameters | Wistar Rats (Group 4) | Iar:COP Rats (Group 6) |
---|---|---|
ESn | 2 | 2 |
NR | 0.18 ± 0.04 | 0.08 ± 0.02 |
DR | 0.28 ± 0.07 | 0.43 ± 0.08 |
ER | 0.54 ± 0.08 | 0.49 ± 0.08 |
kd (h−1) | 0.08 ± 0.01 | 0.08 ± 0.01 |
kt (h−1) | 0.0078 ± 0.0002 | 0.0193 ± 0.0083 |
tlag,d (h) | 0.47 ± 0.09 | 0.35 ± 0.06 |
tlag,e (h) | 3.61 ± 1.53 | 2.58 ± 0.22 |
Group | Formulation | Routes | Animals | Positive AUEC | Negative AUEC |
---|---|---|---|---|---|
1 | Leuprolide solution | IV | Wistar | 208.24 ± 52.30 | −1404.30 ± 287.31 * |
3 | SC | Wistar | 220.87 ± 39.56 | −775.98 ± 289.13 * | |
4 | SR depot | SC | Wistar | 407.91 ± 111.95 | −761.48 ± 292.02 * |
6 | SC | Iar:COP | 354.12 ± 78.95 | −880.28 ± 298.31 * |
Parameters | Wistar Rats | Iar:COP Rats | ||
---|---|---|---|---|
Solution-IV (Group 1) | Solution-SC (Group 3) | SR-SC (Group 4) | SR-SC (Group 6) | |
kin (h−1) | 0.68 | 0.68 | 0.68 | 0.35 |
kout (h−1) | 0.16 | 0.16 | 0.16 | 0.06 |
h | 2.00 ± 0.61 | 2.02 ± 0.05 | 2.00 ± 0.01 | 3.18 ± 1.27 |
Emax | 303.77 ± 12.90 | 183.50 ± 12.87 | 380.00 ± 87.54 | 634.50 ± 144.73 * |
EC50 (ng/mL) | 3.48 ± 1.74 | 6.17 ± 2.49 | 1.80 ± 0.57 | 3.34 ± 0.56 * |
kf,on (h−1) | 0.29 ± 0.19 | 0.14 ± 0.03 | 0.40 ± 0.25 | 0.083 ± 0.14 |
kf,off (h−1) | 0.059 ± 0.017 | 0.02 ± 0.014 | 0.04 ± 0.032 | 0.45 ± 0.04 |
Group | Animal | Route | Formulation | Dose | Sampling time |
---|---|---|---|---|---|
1 | Wistar | IV | Leuprolide solution | 0.1 mg/kg | 0.25, 1, 2, 4, 8 h, 1, 2, 3, 4, 5, 6, 7, 11, 14 days |
2 | Wistar | SC | Dispersion vehicle | 0.2 mL | 8 h, 1, 7, 14 days |
3 | Wistar | SC | Leuprolide solution | 0.1 mg/kg | 0.25, 1, 2, 4, 8 h, 1, 2, 3, 4, 5, 6, 7, 11, 14 days |
4 | Wistar | SC | Lucrin depot dispersion | 0.1 mg/kg (as leuprolide) | 0.25, 1, 2, 4, 8 h, 1, 2, 3, 4, 5, 6, 7, 11, 14 days |
5 | Iar:COP | SC | Dispersion vehicle | 0.2 mL | 8 h, 1, 7, 14 days |
6 | Iar:COP | SC | Lucrin depot dispersion | 0.1 mg/kg (as leuprolide) | 0.25, 1, 2, 4, 8 h, 1, 2, 3, 4, 5, 6, 7, 11, 14 days |
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Lee, D.-S.; Kim, S.-J.; Choi, G.-W.; Lee, Y.-B.; Cho, H.-Y. Pharmacokinetic–Pharmacodynamic Model for the Testosterone-Suppressive Effect of Leuprolide in Normal and Prostate Cancer Rats. Molecules 2018, 23, 909. https://doi.org/10.3390/molecules23040909
Lee D-S, Kim S-J, Choi G-W, Lee Y-B, Cho H-Y. Pharmacokinetic–Pharmacodynamic Model for the Testosterone-Suppressive Effect of Leuprolide in Normal and Prostate Cancer Rats. Molecules. 2018; 23(4):909. https://doi.org/10.3390/molecules23040909
Chicago/Turabian StyleLee, Dong-Seok, Sook-Jin Kim, Go-Wun Choi, Yong-Bok Lee, and Hea-Young Cho. 2018. "Pharmacokinetic–Pharmacodynamic Model for the Testosterone-Suppressive Effect of Leuprolide in Normal and Prostate Cancer Rats" Molecules 23, no. 4: 909. https://doi.org/10.3390/molecules23040909