Table 2.
Clinically used dosing regimens and pharmacokinetic (PK) parameters reported for FDA-approved proteasome inhibitor drugs.
| Drug name | Current clinical dosing regimens | Tested dosing regimens and reported PK parameters
|
References | ||
|---|---|---|---|---|---|
| Tested dosing regimens | PK parameters | Notable characteristics | |||
| Bortezomib (Velcade®, PS-341) | 1.3 mg/m2 IV on days 1, 4, 8 & 11 of 21-day cycles | 1.45 mg/m2, IV (C1D1) | CL, 75.3 (51.2) L/h; Vss, 416 (158) L; t1/2, 8.68 (4.16) h | Phase I trials in patients with advanced solid cancers; dose-proportionality in PK parameters not established | (31) |
|
| |||||
| 1.6 – 2.0 mg/m2, IV (C1D1) | CL, 63.7-112 (29.8-126) L/h; Vss, 696-979 (357-473) L; t1/2, 10.4-14.8 (4.96-10.4) h | ||||
|
| |||||
| 1.3 mg/m2, IV. single dose (C1D1) vs. multiple doses (C1D11, C1D3, & C3D11) |
single dose: CL, 111.6 (73.6) L/h; Vss, 1540 (2730) L; t1/2, 11.5 (12.7) h multiple doses: CL, 18.2-28.0 (9.2-19.8) L/h; Vss, 1613-2213 (1125-2730) L; t1/2, 75.6-108.6 (34.6-64.8) h |
Upon repeated dosing, CL decreased while the systemic exposure and t1/2 increased. | (132) | ||
|
| |||||
| 1.0 mg/m2 IV (C1D11) vs. 2.5 mg/m2 SC (C1D11) |
SC: Cmax, 20.4 (8.87) ng/mL; Tmax, 30 (5–60) min; AUClast, 155 (56.8) ng·h/mL IV: Cmax, 223 (101) ng/mL; Tmax, 2 (2–5) min; AUClast, 151 (42.9) ng37·h/mL |
Phase III study in patients with RRMM. Equivalent systemic exposure between SC and IV groups. | (49, 133) | ||
|
| |||||
| Carfilzomib (Kyprolis®, PR-171) | 20 mg/m2 on days 1 & 2; if tolerated, escalated to 27 mg/m2 (IV infusion, 2-10 min) or 56 mg/m2 (IV infusion, 30 min) on day 8 of cycle 1; followed by tolerated dose on days 9, 15 & 16 of a 28-day cycle and next cycles (additional variations possible in subsequent cycles) |
20 mg/m2, IV (C1D1) | CL, 659 (353) L/h; Vss, 108 (71) L; t1/2, 0.66 (0.48) h | Phase I trial in patients with RRMM. | (65) |
|
| |||||
| 20 mg/m2, 2-10 min IV infusion on D1, 2, 8, 9, 15 & 16 |
D1: CL, 146 (22) L/h D16: CL, 136 (53) L/h |
CL exceeded hepatic blood flow. | (70) | ||
|
| |||||
| 2-10 min IV infusion. 20 mg/m2 on D1 & 2 ➔27 and 36 mg/m2 on D8, 9, 15 & 16 |
20 mg/m2 (D1): CL, 263 (398) L/h; Vss, 27.7 (48.6) L; t1/2, 0.44 (0.15-2.20) h 20 mg/m2 (D16): CL, 136 (52.8) L/h; Vss, 7.75 (3.77) L; t1/2, 1.10 (1.00-1.13) h 27 mg/m2 (D16): CL, 150 (30.9) L/h; Vss, 11.1 (4.45) L; t1/2, 0.35 (0.26-0.92) h |
Phase I/II trials in patients with advanced solid cancers. Rapid systemic CL, large Vss and very short elimination half-lives. |
(69) | ||
|
| |||||
| 30 min IV infusion. 20 mg/m on D1 & 2 ➔ 36, 45, 56 or 70 mg/m2 on D8, 9, 15 & 16 |
20 mg/m2 (C1D1): CL, 143 (56.6†) L/h; t1/2, 0.837 h 27 mg/m2 (C2D16): CL, 102 L/h; t1/2, 0.973 h 56 mg/m2 (C2D16) : CL, 118 (27.7†) L/h; t1/2, 0.875 h |
Phase I trial in patients with RRMM. Comparable PK properties between 30 min and 2-10 min infusion. | (134) | ||
|
| |||||
| 30-min IV infusion. 20 mg/m on D1 ➔ 45, 56, 70 or 88 mg/m2 on D8 & 15 |
20 mg/m2 (D1): CL, 146 (30.4†) L/h; t1/2, 0.64 (0.193-1.29) h; AUClast, 260 (27.6†) ng·h/mL 70 mg/m2 (D15): CL, 131 (28.6†) L/h; t1/2, 0.95 (0.572-1.29) h; AUClast, 1030 (20.5†) ng·h/mL 88 mg/m2 (D15): CL, 138 (34.3†) L/h; t1/2, 0.848 (0.648-0.952) h; AUClast, 1190 (29.1†) ng·h/mL |
Phase I/II trials in patients with RRMM. Dose-proportional increase in AUC. | (135) | ||
|
| |||||
| Ixazomib (Ninlaro®, MLN9708) | 4 mg orally administered on days 1, 8, & 15 of 28-day cycles | 0.24-3.95 mg/m2 on D1, 8 & 15 |
D1: Tmax, 1 (0.5-8.0) h D15: t1/2, 3.6-11.3 days |
Rapid absorption and long terminal half-lives. 2.23 mg/m2 is equivalent to 4.0 mg |
(79) |
|
|
|
||||
| 0.24-2.23 mg/m2 on D1, 4, 8 & 11 of 21-d cycles |
2 mg/m2 (D1): Tmax, 0.65 (0.25-3.97) h 2 mg/m2 (D11): Tmax, 1 (0.5-23.6) h; t1/2, 3.3-7.4 days |
(76) | |||
|
| |||||
| 4 mg on D1, 8 & 15 | CL, 2.0 (4.9‡) L/h; BA, 60%; Tmax, 1.5 (0.3-8) h | Results from population PK modelling. | (136) | ||
|
| |||||
| 4 mg on D1, 8 & 15 | Model parameter: CL, 1.86 L/h; BA, 58%; | Combination treatment with lenalidomide & dexamethasone in RRMM | (81) | ||
Abbreviations: IV, intravenous; SC, subcutaneous; CL, clearance; Vss, volume of distribution at steady-state; t1/2, terminal half-life; Cmax, maximum plasma concentration; Tmax, time to Cmax; AUClast, area under the concentration–time curve from time 0 to the last time point; BA, bioavailability; RRMM, refractory or relapsed multiple myeloma; D, Day(s); C, cycle(s) Values reported as means (standard deviation, % coefficient of variation(†) or % standard error(‡)) except for Tmax and t1/2, which are expressed as median (range).