ith 5th - 95th percentiles) for trastuzumab intravenous infusion dosing regimens in MBC, EBC and AGC patients
Regimen
Primary tumour type
N
Cmin
(µg/mL)
Cmax
(µg/mL)
AUC0-21days
(µg.day/mL)
8mg/kg + 6mg/kg q3w
MBC
805
28.7
(2.9-46.3)
182 (134-280)
1376 (728-1998)
EBC
390
30.9
(18.7-45.5)
176 (127-227)
1390 (1039-1895)
AGC
274
23.1
(6.1-50.3)
132 (84.2-225)
1109 (588-1938)
4mg/kg + 2mg/kg qw
MBC
805
37.4
(8.7-58.9)
76.5 (49.4-114)
1073 (597-1584)
EBC
390
38.9
(25.3-58.8)
76.0 (54.7-104)
1074 (783-1502)
Table 15 Population predicted steady state PK exposure values (median with 5th - 95th percentiles) for trastuzumab intravenous infusion dosing regimens in MBC, EBC and AGC patients
Regimen
Primary tumour type
N
Cmin,ss*
(µg/mL)
Cmax,ss**
(µg/mL)
AUCss, 0-21 days
(µg.day/mL)
Time to steady-state***
(week)
8mg/kg + 6mg/kg q3w
MBC
805
44.2
(1.8-85.4)
179
(123-266)
1736
(618-2756)
12
EBC
390
53.8
(28.7-85.8)
184
(134-247)
1927
(1332-2771)
15
AGC
274
32.9
(6.1-88.9)
131
(72.5-251)
1338
(557-2875)
9
4mg/kg + 2mg/kg qw
MBC
805
63.1
(11.7-107)
107
(54.2-164)
1710
(581-2715)
12
EBC
390
72.6
(46-109)
115
(82.6-160)
1893
(1309-2734)
14
*Cmin,ss – Cmin at steady state
**Cmax,ss = Cmax at steady state
*** time to 90% of steady-state
Table 16 Population predicted PK parameter values at steady state for trastuzumab intravenous infusion dosing regimens in MBC, EBC and AGC patients
Regimen
Primary tumour type
N
Total CL range from Cmax,ss to Cmin,ss
(L/day)
t1/2 range from Cmax,ss to Cmin,ss
(day)
8mg/kg + 6mg/kg q3w
MBC
805
0.183-0.302
15.1-23.3
EBC
390
0.158-0.253
17.5-26.6
AGC
274
0.189-0.337
12.6-20.6
4mg/kg + 2mg/kg qw
MBC
805
0.213-0.259
17.2-20.4
EBC
390
0.184-0.221
19.7-23.2
Trastuzumab washout
Trastuzumab washout period was assessed following q1w or q3w intravenous administration using the population PK model. The results of these simulations indicate that at least 95% of patients will reach concentrations that are <1 µg/mL (approximately 3% of the population predicted Cmin,ss, or about 97% washout) by 7 months.
Circulating shed HER2 ECD
The exploratory analyses of covariates with information in only a subset of patients suggested that patients with greater shed HER2-ECD level had faster nonlinear clearance (lower Km) (P<0.001). There was a correlation between shed antigen and SGOT/AST levels; part of the impact of shed antigen on clearance may have been explained by SGOT/AST levels.
Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBC and EBC patients and no apparent impact on trastuzumab clearance was observed.
5.3 Preclinical safety data
There was no evidence of acute or mult
