Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia
Abstract
:1. Introduction
2. Materials and Methods
2.1. Michaelis–Menten Approximation of Target-Mediated Drug Disposition PK/PD Model Development
2.2. Allometric Scaling and Validation
2.3. Model-Based Simulation of rHuEPO IV and Romiplostim SC Administration PD in Humans
2.4. Software
3. Results
3.1. Michaelis–Menten Approximation of a Target-Mediated Drug Disposition PK/PD Model Reasonably Characterizes the PK and PD Profiles of Romiplostim and rHuEPO as Monotherapy and Combination Therapy
3.2. Extrapolation and VALIDATION of the PK/PD Model to Humans
3.3. Prediction of an Optimal Combination Dosing Regimen in Humans
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameter (Unit) | Description | Value | References |
---|---|---|---|
CLE (L/h) | Clearance of rHuEPO | 0.379 | [21,24] |
KAE (1/h) | Absorption rate of rHuEPO | 0.0269 | |
FE | Bioavailability of rHuEPO | 0.513 | |
V2E (L) | Volume of distribution of the central compartment of rHuEPO | 3.25 | |
V3E (L) | Volume of distribution of the peripheral compartment of rHuEPO | 1.64 | |
QE (L/h) | Tissue distribution clearance of rHuEPO | 0.0993 | |
RTOT (IU/L) | Baseline total receptor | 154.7 | |
KME (IU/L) | Michaelis constant of rHuEPO | 48.1 | |
KINTE (1/h) | Internalization rate constant of rHuEPO | 0.171 | |
KDEGE (1/h) | Degradation rate constant | 0.392 | |
CLR (L/h) | Clearance of romiplostim | 0.183 | [22] |
V2R (L) | Volume of distribution of the central compartment of romiplostim | 4.781 | |
KCPR (1/h) | Intercompartment rate constant of romiplostim | 0.0806 | |
KPCR (1/h) | Intercompartment rate constant of romiplostim | 0.0148 | |
KARM (1/h) | Absorption rate of romiplostim | 0.0254 | |
FRM | Bioavailability of romiplostim | 0.499 | |
KMR (ng/mL) | Michaelis constant of romiplostim | 0.131 | |
ξR (fg/platelet) | Total c-Mpl receptor concentration | 0.0215 | |
KINTR (1/h) | Internalization rate constant of romiplostim | 0.173 |
Regimen Number | Dosing Regimen | Results | Comments |
---|---|---|---|
1 | Romiplostim QW 1 μg/kg for 16 weeks | Platelet count exceeds 0.35 × 1012/L on day 11 | Unacceptable |
2 | Romiplostim 1 μg/kg Q2W from the first week (weeks 1, 3, 5, 7, 9, 11, 13, 15) | Platelet count exceeds 0.35 × 1012/L on day 11 | Unacceptable |
3 | Romiplostim 1μg/kg Q2W from the second week (weeks 2, 4, 6, 8, 10, 12, 14, 16) | Platelet count exceeds 0.35 × 1012/L on day 31 | Unacceptable |
4 | Romiplostim 1 μg/kg Q3W from the first week (weeks 1, 4, 7, 10, 13, 16) | Platelet count exceeds 0.35 × 1012/L on day 11 | Unacceptable |
5 | Romiplostim 1 μg/kg Q3W from the second week (weeks 2, 5, 8, 11, 14) | Platelet count will not exceed 0.35 × 1012/L | Acceptable |
6 | Romiplostim 1 μg/kg Q2W from the third week (weeks 3, 5, 7, 9, 11, 13, 15) | Platelet count exceeds 0.35 × 1012/L on day 50 | Unacceptable |
7 | Romiplostim 1 μg/kg Q4W from the first week (weeks 1, 5, 9, 13) | Platelet count exceeds 0.35 × 1012/L on day 11 | Unacceptable |
8 | Romiplostim 1 μg/kg Q4W from the second week (weeks 2, 6, 10, 14) | Platelet count will not exceed 0.35 × 1012/L | Acceptable (Recommended) |
Parameter | Unit | Estimated Value (Rat) | Scaled Value (Humans) | The Observed Value in Humans |
---|---|---|---|---|
TMP | h | 47.8 [26] | 137.1 | 142 [22] |
TPLT | day | 6.17 [26] | 10.6 | 8–12 [22,33] |
PLT0 | ×1012 cells/L | 0.869 [26] | Fixed to human value | 0.23 [22,28] |
TRET | h | 20 [14] | 44.8 | 57.3 [24,32] |
TRBC | day | 60.8 [14] | 119.6 | 120 [29] |
RBC0 | ×1012 cells/L | 7.38 [14] | Fixed to human value | 4.4 [24,27] |
Parameter | Parameter Explanation | Unit | Value |
---|---|---|---|
TMP | Mean lifespan of megakaryocyte cells | h | 137.1 (scaled) |
TPLT | Mean lifespan of platelets | h | 254.4 (scaled) |
PLT0 | Baseline platelets in blood | ×1012 cells/L | 0.23 (fixed to human value) |
TRBC | Mean residence time for mature RBCs | day | 119.6 (scaled) |
TRET | Mean residence time for RETs | h | 44.8 (scaled) |
RBC0 | Baseline RBCs concentration | ×1012 cells/L | 4.4 (fixed to human value) |
KE | First-order rate constant of MEPs differentiate into BFU-E | ×10−4/h | 6.84 (not scaled) |
KM | First-order rate constant of MEPs differentiate into MK1 | ×10−4/h | 1.18 (not scaled) |
SmaxRM1 | Maximal stimulus of romiplostim on MEPs | Dimensionless | 1.67 (not scaled) |
SmaxRM2 | Maximal stimulus of romiplostim on MK-committed pathway | Dimensionless | 27.8 (not scaled) |
SmaxEPO1 | Maximal stimulus of rHuEPO on MEPs | Dimensionless | 11.3 (not scaled) |
SC50RM | The concentrations of romiplostim that induce a half-maximum effect | ng/mL | 11.9 (not scaled) |
SC50EPO | The concentrations of rHuEPO that induce a half-maximum effect | mIU/mL | 46.9 (not scaled) |
ImaxEPO | Maximal inhibition of rHuEPO on RETs aging rates | Dimensionless | 0.422 (not scaled) |
IC50EPO | The concentration of rHuEPO that induces half-maximum inhibition | mIU/mL | 5.59 (not scaled) |
MCH | Mean corpuscular hemoglobin | pg/cell | 30.2 (fixed to human value) |
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Fan, X.; Krzyzanski, W.; Liu, D.; Wong, R.S.M.; Yan, X. Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia. Pharmaceutics 2023, 15, 344. https://doi.org/10.3390/pharmaceutics15020344
Fan X, Krzyzanski W, Liu D, Wong RSM, Yan X. Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia. Pharmaceutics. 2023; 15(2):344. https://doi.org/10.3390/pharmaceutics15020344
Chicago/Turabian StyleFan, Xiaoqing, Wojciech Krzyzanski, Dongyang Liu, Raymond S. M. Wong, and Xiaoyu Yan. 2023. "Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia" Pharmaceutics 15, no. 2: 344. https://doi.org/10.3390/pharmaceutics15020344
APA StyleFan, X., Krzyzanski, W., Liu, D., Wong, R. S. M., & Yan, X. (2023). Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia. Pharmaceutics, 15(2), 344. https://doi.org/10.3390/pharmaceutics15020344