Daratumumab is a CD38 monoclonal antibody that was recently approved in the US and Canada for the treatment of patients with multiple myeloma (MM) who received three or more prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or who are double-refractory to these agents. In Europe, the drug is approved for relapsed and refractory MM patients whose prior therapy included a PI and an IMiD, and who demonstrated disease progression on the last therapy. |
Following intravenous infusion, daratumumab exhibits nonlinear pharmacokinetic characteristics, consistent with target-mediated drug disposition. |
Administration of daratumumab 16 mg/kg weekly for 8 weeks rapidly saturates target-mediated clearance; dosing every 2 weeks for 16 weeks, and every 4 weeks thereafter is sufficient to maintain target saturation. |
1 Introduction
2 Methods
2.1 Patients and Study Designs
2.1.1 Gen501
2.1.2 SIRIUS
2.2 Pharmacokinetic Analysis
2.3 Statistical Analysis
3 Results
3.1 GEN501 Study
Daratumumab dose (mg/kg) | ||||||||
---|---|---|---|---|---|---|---|---|
0.1 [n = 6] | 0.5 [n = 3] | 1 [n = 6] | 2 [n = 3] | 4 [n = 3] | 8 [n = 3] | 16 [n = 3] | 24 [n = 3] | |
First full infusion
| ||||||||
C
max (μg/mL) | ||||||||
N
| 6 | 3 | 6 | 3 | 3 | 3 | 3 | 3 |
Mean | 0.3 | 4.8 | 20.3 | 38.1 | 83.4 | 153.6 | 405.8 | 500.1 |
SD | 0.3 | 3.7 | 5.9 | 7.4 | 16.0 | 40.8 | 72.5 | 80.4 |
CV (%) | 91.7 | 76.7 | 28.9 | 19.3 | 19.2 | 26.6 | 17.9 | 16.1 |
AUCinf (μg·h/mL) | ||||||||
N
| 0 | 1 | 5 | 3 | 3 | 3 | 3 | 3 |
Mean | 313.3 | 977.2 | 1927.1 | 10,062.9 | 27,916.4 | 56,893.6 | 97,175.7 | |
SD | 758.1 | 373.3 | 6886.0 | 16,155.7 | 22,030.4 | 39,899.9 | ||
CV (%) | 77.6 | 19.4 | 68.4 | 57.9 | 38.7 | 41.1 | ||
CL (mL/h/kg) | ||||||||
N
| 0 | 1 | 5 | 3 | 3 | 3 | 3 | 3 |
Mean | 1.6 | 1.5 | 1.1 | 0.7 | 0.4 | 0.3 | 0.3 | |
SD | 1.0 | 0.2 | 0.8 | 0.3 | 0.1 | 0.2 | ||
CV (%) | 64.0 | 19.1 | 102.7 | 77.7 | 42.4 | 51.7 | ||
t
½ (h) | ||||||||
N
| 0 | 1 | 5 | 3 | 3 | 3 | 3 | 3 |
Mean | 20.0 | 28.3 | 25.6 | 91.5 | 131.8 | 109.9 | 154.7 | |
SD | 17.9 | 5.6 | 59.9 | 68.2 | 42.1 | 36.5 | ||
CV (%) | 63.1 | 21.9 | 65.5 | 51.7 | 38.3 | 23.6 | ||
Last full infusion
| ||||||||
C
max (μg/mL) | ||||||||
N
| 1 | 3 | 2 | 1 | 2 | 3 | 2 | 2 |
Mean | 0.00 | 6.8 | 20.2 | 39.3 | 218.5 | 426.6 | 993.7 | 1163.3 |
SD | 3.8 | 11.9 | 101.3 | 176.6 | 127.0 | 334.0 | ||
CV (%) | 55.6 | 58.9 | 46.3 | 41.4 | 12.8 | 28.7 | ||
AUCinf (μg·h/mL) | ||||||||
N
| 0 | 3 | 2 | 1 | 2 | 2 | 1 | 2 |
Mean | 179.7 | 1345.2 | 4231.7 | 138,149.1 | 186,611.9 | 371,159.3 | 1,018,233.5 | |
SD | 220.8 | 1620.3 | 163,370.0 | 90,617.6 | 1,029,108.4 | |||
CV (%) | 122.9 | 120.4 | 118.3 | 48.6 | 101.1 | |||
CL (mL/h/kg) | ||||||||
N
| 0 | 3 | 2 | 1 | 2 | 3 | 1 | 2 |
Mean | 6.7 | 2.3 | 0.6 | 0.2 | 0.2 | 0.1 | 0.2 | |
SD | 6.2 | 2.6 | 0.1 | 0.1 | 0.1 | |||
CV (%) | 92.0 | 112.5 | 64.7 | 50.0 | 46.5 | |||
t
½ (h) | ||||||||
N
| 0 | 3 | 2 | 1 | 2 | 2 | 1 | 2 |
Mean | 12.7 | 35.7 | 72.1 | 396.5 | 289.5 | 215.3 | 586.6 | |
SD | 12.3 | 37.6 | 408.1 | 121.9 | 486.8 | |||
CV (%) | 97.0 | 105.2 | 102.9 | 42.1 | 83.0 |
Parameter | Daratumumab dose (mg/kg) | |
---|---|---|
8 [n = 30] | 16 [n = 42] | |
C
max (μg/mL) | ||
N
| 28 | 40 |
Mean | 133.5 | 263.4 |
SD | 32.5 | 92.0 |
CV (%) | 24.3 | 34.9 |
AUC0–7 days (μg·h/mL) | ||
N
| 0 | 20 |
Mean | 25,123.3 | |
SD | 10,851.5 | |
CV (%) | 43.2 | |
t
½ (h) | ||
N
| 0 | 19 |
Mean | 216.1 | |
SD | 104.0 | |
CV (%) | 48.2 | |
CL (mL/h/kg) | ||
N
| 0 | 19 |
Mean | 0.4 | |
SD | 0.4 | |
CV (%) | 100.6 | |
V
Z (mL/kg) | ||
N
| 0 | 19 |
Mean | 90.2 | |
SD | 43.4 | |
CV (%) | 48.1 |
3.2 SIRIUS Study
Parameter | Daratumumab 8 mg/kg [n = 18] |
---|---|
Cmax (μg/mL) | |
N
| 18 |
Mean | 138.7 |
SD | 34.9 |
CV (%) | 25.1 |
AUCinf (μg·h/mL) | |
N
| 15 |
Mean | 21,070.0 |
SD | 13,514.3 |
CV (%) | 64.1 |
t
½ (h) | |
N
| 15 |
Mean | 120.7 |
SD | 105.8 |
CV (%) | 87.7 |
CL (mL/h/kg) | |
N
| 15 |
Mean | 0.5 |
SD | 0.3 |
CV (%) | 49.0 |
V
Z (mL/kg) | |
N
| 15 |
Mean | 62.0 |
SD | 18.4 |
CV (%) | 29.7 |