In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III
Abstract
:1. Introduction
2. Results
2.1. PBPK Models (with and without PK Interaction)
2.2. PD (TGI) Models
2.3. PBPK/PD Simulations for Drug Combination
- Case A assumed high tumour growth (kgh), high initial tumour size (SLD0), and a high fraction of sensitive cells.
- Case B assumed a similar approach to that described above, but assumed low tumour growth (kgh).
- Case C assumed high tumour growth (kgh), high initial tumour size (SLD0), and a low fraction of sensitive cells.
- Case D assumed high tumour growth (kgh), low initial tumour size (SLD0), and a high fraction of sensitive cells.
- Scenario 1—without PK and PD drug interactions
- Scenario 2—without PK but with PD drug interactions
- Scenario 3—with PK and without PD drug interactions
- Scenario 4—with PK and PD drug interactions
3. Discussion
4. Materials and Methods
4.1. Clinical Studies Used
4.2. Software
4.3. Statistical Methods
4.4. Resimulation of Clinical PK and PD Data for Siremadlin
Dose (mg) | Regimen | Dosing Schedule | No. of Patients * | No. of Trials | Notes |
---|---|---|---|---|---|
1 | 2A | qdx14 in 28-day cycle | 1 | 10 | |
2 | 2A | qdx14 in 28-day cycle | 2 | 10 | |
4 | 2A | qdx14 in 28-day cycle | 4 | 10 | |
7.5 | 2A | qdx14 in 28-day cycle | 4 | 10 | |
15 | 2A | qdx14 in 28-day cycle | 4 | 10 | |
20 | 2A | qdx14 in 28-day cycle | 5 | 10 | |
15 | 2C | qdx7 in 28-day cycle | 8 | 10 | |
20 | 2C | qdx7 in 28-day cycle | 6 | 10 | |
25 | 2C | qdx7 in 28-day cycle | 5 | 10 | |
12.5 | 1A | qdx1 in 21-day cycle | 1 | 10 | |
25 | 1A | qdx1 in 21-day cycle | 1 | 10 | |
50 | 1A | qdx1 in 21-day cycle | 4 | 10 | |
100 | 1A | qdx1 in 21-day cycle | 4 | 10 | |
200 | 1A | qdx1 in 21-day cycle | 5 | 10 | |
250 | 1A | qdx1 in 21-day cycle | 9 | 10 | Including patients from eltrombopag group (n = 3) |
350 | 1A | qdx1 in 21-day cycle | 5 | 10 | |
120 | 1B | qwx2 (day 1/8) in 28-day cycle | 29 | 10 | |
150 | 1B | qwx2 (day 1/8) in 28-day cycle | 15 | 10 | Including patients from eltrombopag group (n = 7) |
200 | 1B | qwx2 (day 1/8) in 28-day cycle | 3 | 10 |
4.5. Physiologically Based Pharmacokinetic Models
4.5.1. General PBPK Modelling Strategy
4.5.2. Virtual Population Characteristics (System Data)/Patient Population
4.5.3. PBPK Model Verification
4.6. Pharmacodynamic Modelling
4.6.1. General PD (TGI) Modelling Strategy
4.6.2. PD (TGI) Model Development and Verification
4.6.3. Tumour Size Simulation for the Drug Combination
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Dose (mg) | Representative AUC0-inf Predicted (nM × h) | Population AUC0-inf Predicted (nM × h) | AUC0-inf Observed (nM × h) | Representative AUC Predicted/ Observed | Population AUC Predicted/ Observed |
---|---|---|---|---|---|
1 | 257.90 | 286.40 (44.8%) | 241.80 (-%) | 1.07 | 1.18 |
2 | 515.80 | 537.83 (42.5%) | 304.46 (31.5%) | 1.69 | 1.77 |
4 | 1031.60 | 1073.86 (36.5%) | 387.64 (22.0%) | 2.66 | 2.77 |
7.5 | 1934.26 | 2013.49 (36.5%) | 1076.86(49.8%) | 1.80 | 1.87 |
12.5 | 3223.76 | 3580.00 (44.8%) | 2670.28 (-%) | 1.21 | 1.34 |
15 | 3868.52 | 3816.39 (40.0%) | 2343.49 (71.0%) | 1.65 | 1.63 |
20 | 5158.02 | 5119.24 (36.9%) | 4122.18 (29.6%) | 1.25 | 1.24 |
25 | 6447.53 | 6399.05 (36.9%) | 4803.12 (28.3%) | 1.34 | 1.33 |
50 | 12,895.05 | 13,423.28 (36.5%) | 14,455.63 (25.6%) | 0.89 | 0.93 |
100 | 25,790.10 | 26,846.56 (36.5%) | 25,723.34 (58.5%) | 1.00 | 1.04 |
120 | 30,948.13 | 29,889.60 (38.8%) | 33,275.78 (62.7%) | 0.93 | 0.90 |
150 | 38,685.16 | 37,968.46 (41.8%) | 42,719.97 (43.2%) | 0.91 | 0.89 |
200 | 51,580.21 | 51,192.34 (36.9%) | 47,271.75 (56.2%) | 1.09 | 1.08 |
250 | 64,475.26 | 63,698.83 (43.2%) | 74,579.68 (71.2%) | 0.86 | 0.85 |
350 | 90,265.34 | 89,586.57 (36.9%) | 99,211.21 (34.4%) | 0.91 | 0.90 |
Dose (mg) | Representative Cmax Predicted (nM) | Population Cmax Predicted (nM) | Cmax Observed (nM) | Representative Cmax Predicted/ Observed | Population Cmax Predicted/ Observed |
---|---|---|---|---|---|
1 | 14.37 | 14.05 (33.6%) | 14.22 (-%) | 1.01 | 0.99 |
2 | 28.75 | 28.77 (27.5%) | 21.61 (23.7%) | 1.33 | 1.33 |
4 | 57.49 | 58.14 (27.0%) | 31.69 (22.8%) | 1.81 | 1.83 |
7.5 | 107.79 | 109.01 (27.0%) | 70.22 (43.9%) | 1.54 | 1.55 |
12.5 | 179.64 | 175.62 (33.6%) | 212.46 (-%) | 0.85 | 0.83 |
15 | 215.60 | 209.79 (26.2%) | 164.74 (56.9%) | 1.31 | 1.27 |
20 | 266.36 | 278.51 (28.6%) | 269.17 (20.3%) | 0.99 | 1.03 |
25 | 359.32 | 348.15 (28.6%) | 422.57 (27.5%) | 0.85 | 0.82 |
50 | 718.63 | 726.77 (27.0%) | 840.82 (13.0%) | 0.85 | 0.86 |
100 | 1437.19 | 1453.48 (27.0%) | 1194.25 (30.1%) | 1.20 | 1.22 |
120 | 1724.76 | 1596.25 (26.2) | 1871.59 (51.5%) | 0.92 | 0.85 |
150 | 2156.00 | 2093.20 (25.4%) | 2600.42 (27.8%) | 0.83 | 0.80 |
200 | 2874.55 | 2785.12 (28.6%) | 2104.39 (43.7%) | 1.37 | 1.32 |
250 | 3593.23 | 3482.48 (27.4%) | 3629.21 (69.5%) | 0.99 | 0.96 |
350 | 5030.18 | 4873.72 (28.6%) | 4066.91 (56.9%) | 1.24 | 1.20 |
Drug | Trametinib | Trametinib | Trametinib | Trametinib |
---|---|---|---|---|
Representative AUC0–24 h (day 1) | 165.39 | - | - | - |
Population AUC0–24 h (day 1) | 170.70 (29%) | - | 200.76 (20%) * | 109.60 (2%) ** |
Representative AUC0–24 h (day 15) | 570.91 | - | - | - |
Population AUC0–24 h (day 15) | 656.45 (50%) | 601.24 (22%) | - | 586.28 (16%) ** |
Population AUC ratio (day 1) | - | - | 0.85 | 1.56 |
Population AUC ratio (day 15) | - | 1.09 | - | 1.12 |
Representative Cmax (day 1) | 18.08 | - | - | - |
Population Cmax (day 1) | 18.50 (19%) | - | 24.44 (3%) * | 10.45 (0.3%) ** |
Representative Cmax (day 15) | 36.44 | - | - | - |
Population Cmax (day 15) | 40.93 (36%) | 36.07 (28%) | - | 31.67 (12%) ** |
Population Cmax ratio (day 1) | - | - | 0.76 | 1.77 |
Population Cmax ratio (day 15) | - | 1.13 | - | 1.29 |
Source | Current study | Digitised from Infante et al. [32] | Digitised from Ho et al. [30] | Digitised from Ouellet et al. [31] |
Drug | Siremadlin | Trametinib |
---|---|---|
Dose (mg) | 120 | 2 |
AUC no PK DDI | 19,240.73 | 174.01 |
AUC PK DDI | 21,858.34 | 133.15 |
AUC ratio (PK DDI) | 1.1360 | 0.7652 |
Cmax no PK DDI | 1724.96 | 19.02 |
Cmax PK DDI | 2580.39 | 9.61 |
Cmax ratio (PK DDI) | 1.4959 | 0.5051 |
Trial | n | No. of Trials | Difference (Drug Combination vs. Trametinib) | %ORR (Mean from 10 Trials) | Statistical Significance (p Value) |
---|---|---|---|---|---|
Siremadlin Case A | 29 | 10 | 51.64% | 0.00% | <0.0001 |
Trametinib Case A | 214 | 10 | 0.00% | 51.64% | <0.0001 |
Case 1a | 243 | 10 | 26.51% | 78.15% | <0.0001 |
Case 2a | 243 | 10 | 31.16% | 82.80% | <0.0001 |
Case 3a | 243 | 10 | 45.81% | 97.45% | <0.0001 |
Case 4a | 243 | 10 | 47.29% | 98.93% | <0.0001 |
Siremadlin Case B | 29 | 10 | 25.84% | 0.00% | <0.0001 |
Trametinib Case B | 214 | 10 | 0.00% | 25.84% | <0.0001 |
Case 1b | 243 | 10 | 26.67% | 52.51% | <0.0001 |
Case 2b | 243 | 10 | 30.70% | 56.54% | <0.0001 |
Case 3b | 243 | 10 | 52.22% | 78.07% | <0.0001 |
Case 4b | 243 | 10 | 59.14% | 84.98% | <0.0001 |
Siremadlin Case C | 29 | 10 | 51.64% | 0.00% | <0.0001 |
Trametinib Case C | 214 | 10 | 0.00% | 51.64% | <0.0001 |
Case 1c | 243 | 10 | 14.41% | 66.05% | <0.0001 |
Case 2c | 243 | 10 | 20.83% | 72.47% | <0.0001 |
Case 3c | 243 | 10 | 42.52% | 94.16% | <0.0001 |
Case 4c | 243 | 10 | 45.81% | 97.45% | <0.0001 |
Siremadlin Case D | 29 | 10 | 51.64% | 0.00% | <0.0001 |
Trametinib Case D | 214 | 10 | 0.00% | 51.64% | <0.0001 |
Case 1d | 243 | 10 | 26.51% | 78.15% | <0.0001 |
Case 2d | 243 | 10 | 31.16% | 82.80% | <0.0001 |
Case 3d | 243 | 10 | 45.81% | 97.45% | <0.0001 |
Case 4d | 243 | 10 | 47.29% | 98.93% | <0.0001 |
Drug | Siremadlin | Trametinib | Trametinib | Trametinib | Trametinib |
---|---|---|---|---|---|
NCT number | NCT02143635 | NCT00687622 | NCT01387204 | NCT01245062 | NCT00687622/ NCT01037127/ NCT01245062 |
Phase | 1/2 | 1/2 | 1 | 3 | 1/2/3 |
Doses (mg) | 1–350 | 0.125–10 | 2 | 2 | 0.125–10/2/2 |
Administration | Oral | Oral | Oral | Oral | Oral/oral/oral |
n | 115 | 206 | 2 | 214 | 206/97/214 |
Women (%) | 44 | 46 | 0 | 44 | 46/30/44 |
Age (Years) | 18–80 | 19–92 | 54–66 | 23–85 | 19–92/23–79/ 23–85 |
Dataset purpose | PK/PD training/ verification | PK training | PK training | PD training/ verification | PK verification |
Reference | Guerreiro et al. [29] Stein et al. [36] Jeay et al. [39] | Infante et al. [32] | Ho et al. [30] | Flaherty et al. [35] Mistry et al. [34] | Ouellet et al. [31] |
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Witkowski, J.; Polak, S.; Pawelec, D.; Rogulski, Z. In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III. Int. J. Mol. Sci. 2023, 24, 2239. https://doi.org/10.3390/ijms24032239
Witkowski J, Polak S, Pawelec D, Rogulski Z. In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III. International Journal of Molecular Sciences. 2023; 24(3):2239. https://doi.org/10.3390/ijms24032239
Chicago/Turabian StyleWitkowski, Jakub, Sebastian Polak, Dariusz Pawelec, and Zbigniew Rogulski. 2023. "In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III" International Journal of Molecular Sciences 24, no. 3: 2239. https://doi.org/10.3390/ijms24032239