Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment
Abstract
:1. Introduction
2. Materials and Methods
2.1. Software and Information Resources
2.2. Model Development
Parameter | Unit | Input Value | Reported Value | Reference |
---|---|---|---|---|
Physicochemical properties | ||||
Molecular weight | g/mol | 457.493 | 457.493 | [24] |
Effective molecular weight | g/mol | 406.5 | PK-Sim | |
Lipophilicity | Log | 5.73 | 5.73, 6.45 | [24] |
pKa | 4.26 | 4.26 | [24] | |
Solubility | mg/mL | 0.000477 | 0.000477 | [25] |
Plasma protein binding | % | 97.9 | 97.9 | [25] |
Absorption | ||||
Intestinal permeability | cm/min | 0.02 | Calculated | |
Dissolution model | Weibull | PK-Sim | ||
Dissolution time (50% dissolved) | min | 120 | Optimized | |
Distribution | ||||
Partition coefficient model | Rodger and Roland | PK-Sim | ||
Cellular permeability model | PK-Sim | PK-Sim | ||
Fraction unbound | % | 2.10 | [25] | |
Blood to plasma ratio | 0.66 | 0.66 | [16] | |
Enzymatic biotransformation Process type: In vitro metabolic rate in presence of recombinant enzymes | ||||
CYP2C8 | µL/min/pmol | 0.01157 | [16] | |
CYP2C9 | µL/min/pmol | 0.08525 | [16] | |
CYP3A4 | µL/min/pmol | 0.01640 | [16] | |
CYP2J2 | µL/min/pmol | 0.01872 | [16] | |
CYP2C19 | µL/min/pmol | 0.01331 | [16] | |
Parameterization of enzyme inhibition process | ||||
Ki for fluconazole-CYP3A4 complex | µmol/L | 10.7 | [32] | |
Ki for fluconazole-CYP2C9 complex | µmol/L | 19.60 | [33] | |
Ki for fluconazole-CYP2C19 complex | µmol/L | 1.74 | [33] | |
Parameterization of enzyme induction process | ||||
EC50 for rifampicin-CYP3A4 complex | µmol/L | 0.34 | 0.34 | [34] |
Emax for rifampicin-CYP3A4 complex | 9 | 9 | [34] | |
EC50 for rifampicin-CYP2C8 complex | µmol/L | 0.34 | 0.34 | [35] |
Emax for rifampicin-CYP2C8 complex | 3.2 | 3.2 | [35] |
2.3. Etrasimod PBPK Model Development and Verification in Adult Healthy Population
2.4. Modeling the Effect of Drug Interactions on the Etrasimod Pharmacokinetic
2.5. Modeling the Effect of Hepatic Impairment on the Etrasimod Pharmacokinetic
Model Parameter | Severity of Liver Disease | ||
---|---|---|---|
Child–Pugh A | Child–Pugh B | Child–Pugh C | |
Portal vein blood flow a | 0.40 | 0.36 | 0.04 |
Hepatic arterial blood flow a | 1.3 | 2.3 | 3.4 |
Renal blood flow a | 0.88 | 0.65 | 0.48 |
Cardiac index a | 1.11 | 1.27 | 1.36 |
Blood flow in other organs a | 1.75 | 2.25 | 2.75 |
Albumin a | 0.81 | 0.68 | 0.50 |
Alpha-1-acid glycoprotein a | 0.60 | 0.56 | 0.30 |
Hematocrit a | 0.39 | 0.37 | 0.35 |
Functional liver mass a | 0.69 | 0.55 | 0.28 |
GFR a | 1 | 0.70 | 0.36 |
CYP3A4 activity b | 1 | 0.40 | 0.40 |
CYP2J2 activity b | 1 | 1 | 1 |
CYP2C8 activity c | 0.69 | 0.52 | 0.33 |
CYP2C9 activity c | 0.69 | 0.52 | 0.33 |
CYP2C19 activity c | 0.32 | 0.26 | 0.12 |
2.6. Dosing Adjustment of Etrasimod Based on the Severity of the Liver Impairment
3. Results
3.1. Development of the Etrasimod PBPK Model in an Adult Healthy Population
3.2. Modeling the Effect of Drug Interaction on the Etrasimod Exposure
3.3. Modeling the Effect of Hepatic Impairment on the Etrasimod Pharmacokinetics
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Dose | N (male %) | Age (year) | Weight (kg) | AUC_inf [ng·h/mL] | Cmax [ng/mL] | Ref. |
---|---|---|---|---|---|---|
Phase 1, open label, single dose study to build and refine the model | ||||||
1 mg | 18 (68.4) | 32 (8.1) | 75.7 (11.4) | 763 (207) | 18.8 (3.3) | [26] |
Phase 1, open label, single dose study to build and refine the model a | ||||||
1 mg | 19 (73.7) | 35.3 (10.4) | 73.5 (14.2) | 759 (196) | 19 (4.4) | [27] |
1 mg | 19 (36.8) | 36.4 (10.6) | 77.1 (16.5) | 802 (232) | 19.5 (5.0) | |
2 mg | 18 (83.3) | 39.4 (9.1) | 80.6 (9.5) | 1510 (488) | 34.2 (11.1) | |
Phase 1, open label, single dose study to build and refine the model | ||||||
2 mg | 8 (100) | 31 (6.6) | 77.3 (11.48) | 1900 (596) | 42.5 (10.2) | [16] |
Phase 1, randomized, double-blind, SAD study to verify the model | ||||||
0.1 mg | 6 (66.7) | 27.3 (5.8) | 27.8 ± 4.6 (BMI) | 79.8 (21.3) | 1.7 (0.6) | [28] |
0.35 mg | 6 (33.3) | 25.8 (4.4) | 30.0 ± 4.9 (BMI) | 268 (31.0) | 6.3 (0.4) | |
1 mg | 6 (50.0) | 31.5 (6.4) | 29.3 ± 3.8 (BMI) | 793 (168) | 17.2 (5.5) | |
3 mg | 6 (66.7) | 31.0 (7.1) | 27.2 ± 4.7 (BMI) | 2600 (840) | 60.5 (11.7) | |
5 mg | 6 (33.3) | 33.0 (9.4) | 27.2 ± 6.4 (BMI) | 4390 (610) | 102 (19.1) | |
Phase 1, randomized, double-blind, MAD study to verify the model. PK parameters after the last dose | ||||||
0.7 mg | 10 (50.0) | 34.2 (8.8) | 28.9 ± 4.5 (BMI) | 596 (121) | 30.8 (6.6) | [28] |
1.35 mg | 10 (30.0) | 31.4 (9.0) | 26.9 ± 3.1 (BMI) | 1197 (226) | 63.5 (11.8) | |
2 mg | 10 (40.0) | 30.1 (7.0) | 27.0 ± 5.8 (BMI) | 2163 (489) | 113 (27.5) | |
0.35 mg/2 mg | 10 (50.0) | 32.8 (6.0) | 27.2 ± 2.1 (BMI) | 1513 (359) | 80.5 (17.4) | |
0.5 mg/3 mg | 10 (40.0) | 29.0 (7.2) | 27.7 ± 2.2 (BMI) | 2867 (376) | 151 (19.0) | |
Phase 1, randomized, double-blind, MAD study to verify the model. PK parameters after the last dose | ||||||
2 mg/3 mg/4 mg | 30 | 18–55 | 50–100 | 2885 (793) | 163 (46.7) | [29] |
Group | Data | AUC_inf [ng·h/mL] | Cmax [ng/mL] | T½ [h] |
---|---|---|---|---|
Effect of enzymes inhibition | ||||
Control † | Predicted | 875 | 17.7 | 44.0 |
Observed | 759 | 19.0 | 42.5 | |
Fold error | 1.15 | 0.93 | 1.04 | |
Etrasimod + Fluconazole | Predicted | 1772 | 20.0 | 82.1 |
Observed | 1440 | 21.4 | 88.2 | |
Fold error | 1.23 | 0.93 | 0.70 | |
Pred. AUCR | 2.03 | |||
Obs. AUCR | 1.90 | |||
Pred/Obs AUCR | 1.07 | |||
Pred. CmaxR | 1.13 | |||
Obs. CmaxR | 1.13 | |||
Pred/Obs CmaxR | 1.0 | |||
Pred. T½R | 1.87 | |||
Obs. T½R | 2.08 | |||
Pred/Obs T½R | 0.90 | |||
Effect of enzymes induction | ||||
Control ‡ | Predicted | 1750 | 34.3 | 44.0 |
Observed | 1510 | 34.2 | 41.1 | |
Fold error | 1.16 | 1.0 | 1.10 | |
Etrasimod + Rifampicin | Predicted | 754 | 24.0 | 17.0 |
Observed | 770 | 36.0 | 21.0 | |
Fold error | 0.98 | 0.67 | 0.81 | |
Pred. AUCR | 0.43 | |||
Obs. AUCR | 0.51 | |||
Pred/Obs AUCR | 0.84 | |||
Pred. CmaxR | 0.70 | |||
Obs. CmaxR | 1.05 | |||
Pred/Obs CmaxR | 0.67 | |||
Pred. T½R | 0.40 | |||
Obs. T½R | 0.51 | |||
Pred/Obs T½R | 0.78 |
Parameter | Population | Observed | Predicted | Fold Error |
---|---|---|---|---|
AUC_inf (ng·h/mL) | Healthy | 1510 a | 1750 | 1.16 |
CP-A | 1706 (13% ↑) b | 1894 (12.50% ↑) | 1.11 | |
CP-B | 1948 (29% ↑) b | 2208 (28.40% ↑) | 1.13 | |
CP-C | 2371 (57%↑) b | 2526 (52.4% ↑) | 1.07 |
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Alasmari, M.S.; Alqahtani, F.; Alasmari, F.; Alsultan, A. Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment. Pharmaceutics 2024, 16, 1540. https://doi.org/10.3390/pharmaceutics16121540
Alasmari MS, Alqahtani F, Alasmari F, Alsultan A. Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment. Pharmaceutics. 2024; 16(12):1540. https://doi.org/10.3390/pharmaceutics16121540
Chicago/Turabian StyleAlasmari, Mohammed S., Faleh Alqahtani, Fawaz Alasmari, and Abdullah Alsultan. 2024. "Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment" Pharmaceutics 16, no. 12: 1540. https://doi.org/10.3390/pharmaceutics16121540
APA StyleAlasmari, M. S., Alqahtani, F., Alasmari, F., & Alsultan, A. (2024). Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment. Pharmaceutics, 16(12), 1540. https://doi.org/10.3390/pharmaceutics16121540