gintravenous trastuzumab. Total trastuzumab clearance increases with decreasing concentrations due to parallellinear and non-linear elimination pathways.
Although the average trastuzumab exposure was higher following the first cycle in breast cancer patientsreceiving the three-weekly schedule compared to the weekly schedule of trastuzumab, the averagesteady-state exposure was essentially the same at both dosages. The average trastuzumab exposurefollowing the first cycle and at steady state as well as the time to steady state was higher in breast cancerpatients compared to MGC patients at the same dosage; however, the reason for this exposure difference isunknown. Additional predicted trastuzumab exposure and PK parameters following the first trastuzumabcycle and at steady state exposure are described in Tables 7 and 8, respectively.
Population PK based simulations indicate that following discontinuation of trastuzumab, concentrations inat least 95% of breast cancer and MGC patients will decrease to approximately 3% of the populationpredicted steady-state trough serum concentration (approximately 97% washout) by 7 months [seeWarnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].
Table 7
Population Predicted Cycle 1 PK Exposures (Median with 5th – 95th Percentiles) in Breast Cancer and MGC
Patients
Schedule Primary tumor
type N
Cmin
(µg/mL)
Cmax
(µg/mL)
AUC0 -21days
(µg.day/mL)
8 mg/kg +
6 mg/kg q3w
Breast cancer 1195 29.4
(5.8 - 59.5)
178
(117 - 291)
1373
(736 - 2245)
MGC 274 23.1
(6.1 - 50.3)
132
(84.2 - 225)
1109
(588 - 1938)
4 mg/kg +
2 mg/kg qw Breast cancer 1195 37.7
(12.3 - 70.9)
88.3
(58 - 144)
1066
(586 - 1754)
Table 8
Population Predicted Steady State PK Exposures (Median with 5th - 95th Percentiles) in Breast Cancer and MGC
Patients
Schedule Primary
tumor type N
Cmin,ssa
(µg/mL)
Cmax,ssb
(µg/mL)
AUCss, 0-21 days
(µg.day/mL)
Time to
steadystate
(week)
Total CL
range at
steady-state
(L/day)
8 mg/kg +
6 mg/kg
q3w
Breast
cancer
1195 47.4
(5 - 115)
179
(107 - 309)
1794
(673 - 3618)
12 0.173 - 0.283
MGC 274 32.9
(6.1 - 88.9)
131
(72.5 - 251)
1338
(557 - 2875)
9 0.189 - 0.337
4 mg/kg +
2 mg/kg qw
Breast cancer 1195 66.1
(14.9 - 142)
109
(51.0 - 209)
1765
(647 - 3578)
12 0.201 - 0.244
a Steady-state trough serum concentration of trastuzumab b Maximum steady-state serum concentration of trastuzumabSpecific Populations: Based on a population pharmacokinetic analysis, no clinically significantdifferences were observed in the pharmacokinetics of trastuzumab based on age (< 65 (n = 1294); ≥ 65(n = 288)), race (Asian (n = 264); non-Asian (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 pharmacokineticsof trastuzumab products in patients with severe renal impairment, end-stage renal disease with or withouthemodialysis, or hepatic impairment is unknown.
Drug Interaction Studies:
There have been no formal drug interaction studies performed with trastuzumab products in humans.
Clinically significant interactions between trastuzumab and concomitant medications used in clinical trialshave not been observed.
Paclitaxel and doxorub |
