bcutaneous administration of HERCEPTIN HYLECTA 600 mg every 3weeks as compared to intravenous trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance every 3 weeks in theHannaH Study is shown in Table 6. The pharmacokinetic (PK) results for the co-primary endpoint, Ctrough predoseCycle 8, showed non-inferiority of HERCEPTIN HYLECTA (78.7 mcg/mL) compared to intravenoustrastuzumab (57.8 mcg/mL), with a geometric mean ratio of 1.3 (90% CI: 1.2–1.4).
A population PK model with parallel linear and nonlinear elimination from the central compartment wasconstructed using pooled HERCEPTIN HYLECTA and intravenous trastuzumab pharmacokinetic (PK) data fromHannaH to describe the observed trastuzumab PK concentrations following HERCEPTIN HYLECTAsubcutaneous administration and intravenous trastuzumab administration. Population PK predicted trastuzumabexposure are shown in Table 6.
Following subcutaneous administration of HERCEPTIN HYLECTA, trastuzumab concentrations wereapproximately at steady-state after the Cycle 7 dose with < 15% increase in concentration up to Cycle 13. Themean Ctrough at the pre-dose Cycle 18 in HERCEPTIN HYLECTA arm is similar to that of Cycle 13, suggestingno further increase after Cycle 13. The mean Cmax was 32% lower, and the mean AUC0-21 days following the Cycle7 dose and Cycle 12 dose was approximately 10% and 20% higher, respectively, in the HERCEPTIN HYLECTA
arm than in the intravenous trastuzumab arm.
Table 6
Trastuzumab Exposure (median with 5th-95th Percentiles) following SubcutaneousAdministration of HERCEPTIN HYLECTA or Intravenous Trastuzumab
Trastuzumab Exposure HERCEPTIN HYLECTA Intravenous Trastuzumab
Ctrough (mcg/mL) Cycle 1 28.2 (14.8–40.9) 29.4 (5.8–59.5)
Cycle 7 75.0 (35.1–123) 47.4 (5–114.7)
Cmax (mcg/mL) Cycle 1 79.3 (56.1–109) 178 (117–291)
Cycle 7 149 (86.1–214) 179 (107–309)
AUC0-21 days (mcg/mL•day) Cycle 1 1065 (718–1504) 1373 (736–2245)
Cycle 7 2337 (1258–3478) 1794 (673–3618)
General PK parameters of trastuzumab following subcutaneous administration of HERCEPTIN HYLECTA areshown in Table 7. Trastuzumab is estimated to reach concentrations that are < 1 mcg/mL by 7 months in at least95% patients.
Table 7
PK parameters of Trastuzumab following Subcutaneous
Administration of HERCEPTIN HYLECTA *
Absorption
Absolute Bioavailability 0.77 (13)
First-order absorption rate, ka (day-1
) 0.4 (2.92) †
Tmax (day) 3 (1-14) ‡
Distribution
Volume of Central Compartment (L) 2.9 (19.1)
Elimination
Linear Elimination Clearance (L/day) 0.11 (30)
Non-linear Elimination Vmax (mg/day) 11.9 (19.9) †
Non-linear Elimination Km (mg/L) 33.9 (38.6) †
* Parameters represented as geometric mean (%CV) unless otherwise specified
† Residual standard error
‡ Median (range)
Specific Populations
Body weight showed a statistically significant influence on PK. In patients with a body weight < 51 kg, meansteady state AUC of trastuzumab was about 80% higher after HERCEPTIN HYLECTA than after intravenoustrastuzumab treatment, whereas in the highest BW group (> 90 kg) AUC was 20% lower after HERCEPTINHYLECTA than after intravenous trastuzumab treatment. However, no body weight based dose adjustments areneeded, as the exposure changes are not considered clinically re |
