stuzumab cycle and at steady state exposure aredescribed in Tables 7 and 8, respectively.
Population PK based simulations indicate that following discontinuation of trastuzumab, concentrations in atleast 95% of breast cancer patients and MGC patients will decrease to approximately 3% of the populationpredicted steady-state trough serum concentration (approximately 97% washout) by 7 months [see Warningsand Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].
Table 7
Population Predicted Cycle 1 PK Exposures (Median with 5th to 95th Percentiles) in Breast Cancer and MGCPatients
Schedule Primary tumor
type
N Cmin
(µg/mL)
Cmax
(µg/mL)
AUC0-21 days
(µg.day/mL)
8 mg/kg + 6 mg/kg Breast cancer 1195 29.4
(5.8 to 59.5)
178
(117 to 291)
1373
(736 to 2245)
q3w MGC 274 23.1
(6.1 to 50.3)
132
(84.2 to 225)
1109
(588 to 1938)
4 mg/kg + 2 mg/kg
qw
Breast cancer 1195 37.7
(12.3 to 70.9)
88.3
(58 to 144)
1066
(586 to 1754)
Table 8
Population Predicted Steady State PK Exposures (Median with 5th to 95th Percentiles) in Breast Cancerand MGC Patients
Schedule Primary
tumor
type
N Cmin,ssa
(µg/mL)
Cmax,ss
b
(µg/mL)
AUCss, 0-21 days
(µg.day/mL)
Time
to
steadystate
(week)
Total CL
range at
steady-state
(L/day)
8 mg/kg + Breast 119 47.4 179 1794 12 0.173 to 0.283
6 mg/kg cancer 5 (5 to 115) (107 to 309) (673 to 3618)
q3w MGC 274 32.9 131 1338 9 0.189 to 0.337
(6.1 to 88.9) (72.5 to 251) (557 to 2875)
4 mg/kg + Breast 119 66.1 109 1765 12 0.201 to 0.244
2 mg/kg cancer 5 (14.9 to 142) (51.0 to 209) (647 to 3578)
qw
a Steady-state trough serum concentration of trastuzumab
b Maximum steady-state serum concentration of trastuzumab
Specific Populations
Based on a population pharmacokinetic analysis, no clinically significant differences were observed in thepharmacokinetics of trastuzumab based on age (<65 (n = 1294); ≥65 (n = 288)), race (Asian (n = 264); nonAsian(n = 1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n = 636) or
moderate (CLcr 30 to 60 mL/min) (n = 133)). The pharmacokinetics of trastuzumab products in patients withsevere renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment areunknown.
Drug Interaction Studies
There have been no formal drug interaction studies performed with trastuzumab products in humans. Clinicallysignificant interactions between trastuzumab and concomitant medications used in clinical trials have not beenobserved.
Paclitaxel and Doxorubicin
Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH],and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used ascombination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combinationtherapy.
Docetaxel and Carboplatin
When trastuzumab was administered in combination with docetaxel or carboplatin, neither the plasmaconcentrations of docetaxel or carboplatin nor the plasma concentrations of trastuzumab were altered.
Cisplatin and Capecitabine
In a drug interaction substudy conducted in patients in Study 7, the pharmacokinetics of cisplatin, capecitabineand their metabolites were not altered when administered in co
