Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2    Pharmacodynamics

Cardiac Electrophysiology
The administration of multiple doses of ENHERTU (6.4 mg/kg every 3 weeks did not show large mean effect (i.e. >20 ms) on the QTc interval in an open label, single-arm study in 51 patients with metastatic HER2-positive cancer.

Pharmacokinetic Properties

12.3    Pharmacokinetics

The pharmacokinetics of trastuzumab deruxtecan was evaluated in patients with cancer. Following a single dose, exposures (Cmax and AUC) of trastuzumab deruxtecan and released topoisomerase inhibitor (DXd) increased proportionally over a dose range of 3.2 mg/kg to 8 mg/kg (approximately 0.6 to 1.5 times the recommended dose in breast cancer and NSCLC and 0.5 to 1.25 times the recommended dose in gastric cancer).


Metastatic Breast Cancer

At the recommended dosage of ENHERTU for patients with metastatic breast cancer, the estimated geometric mean (coefficient of variation [CV]%) Cmax ss of trastuzumab deruxtecan and DXd were 133 µg/mL (19%) and 4.7 ng/mL (43%), respectively, and the corresponding AUC ss were 780 µg day/mL (27%) and 29 ng·day/mL (42%),. Accumulation of trastuzumab deruxtecan was approximately 35% at steady state (Cycle 3).

Unresectable or Metastatic HER2-Mutant NSCLC
At the recommended dosage of ENHERTU for patients with HER2-mutant NSCLC, the estimated geometric mean (CV%) Cmax,ss of fam-trastuzumab deruxtecan-nxki and DXd were 141 μg/mL (21%) and 7.2 ng/mL (44%), respectively, and the corresponding AUCss were 775 μg·day/mL (33%) and 40.9 ng·day/mL (43%), respectively, based on population pharmacokinetic analysis. Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 31% at steady-state.


Locally Advanced or Metastatic Gastric Cancer
At the recommended dosage of ENHERTU for patients with HER2-positive gastric cancer, the estimated geometric mean (CV%) Cmax,ss of trastuzumab deruxtecan and DXd were 126 µg/mL (18%) and 5.2 ng/mL (42%), respectively, and the corresponding AUCss were 743 µg·day/mL (26%) and 33 ng·day/mL (43%). Accumulation of trastuzumab deruxtecan was approximately 39% at steady-state (Cycle 3).


Distribution
Based on population pharmacokinetic analysis, the estimated volume of distribution of the central compartment (Vc) of trastuzumab deruxtecan was 2.68 L.

For humans, DXd plasma protein binding is approximately 97% and the blood-to-plasma ratio is approximately 0.6, in vitro.

Elimination

The median elimination half-life (t1/2) of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer, HER2-mutant NSCLC, and HER2-positive gastric cancer was approximately 5.4-5.7 days. The estimated systemic clearance of trastuzumab deruxtecan was 0.41 L/day.

The median apparent elimination half-life (t1/2) of DXd in patients with HER2-positive metastatic breast cancer, HER2- mutant NSCLC, and HER2-positive gastric cancer was approximately 5.4-5.7 days. The estimated apparent systemic clearance of DXd was 18.3 L/h.

Metabolism
The humanized HER2 IgG1 monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

In vitro, DXd is primarily metabolized by CYP3A4.

Specific Populations
No clinically significant differences in the pharmacokinetics of trastuzumab deruxtecan or DXd were observed for age (20- 96 years), race (Asian [White or Black ), sex, body weight (27-125 kg), mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), mild or moderate renal impairment.
The pharmacokinetics of trastuzumab deruxtecan or DXd in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST) or severe renal impairment (CLcr <30 mL/min) is unknown.

Drug Interaction Studies

Clinical Studies
Effect of CYP3A Inhibitors on DXd: Coadministration of itraconazole, a strong CYP3A inhibitor, with multiple doses of ENHERTU increased steady state AUC0-17 days of trastuzumab deruxtecan by 11% and DXd by 18%. The impact of these changes is not clinically meaningful.

Effect of OATP Inhibitors on DXd: Coadministration of ritonavir, a dual inhibitor of OATP1B/CYP3A, with multiple doses of ENHERTU increased steady state AUC0-17 days of trastuzumab deruxtecan by 19% and DXd by 22%. The impact of these changes is not clinically meaningful.

In Vitro Studies

Effects of DXd on CYP Enzymes: DXd does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A nor induce CYP1A2, CYP2B6, or CYP3A.

Effects of DXd on Transporters: At clinically relevant concentrations (steady-state Cmax of ~0.2 μmol/L), DXd has a low potential to inhibit OAT1 (IC50 value of 12.7 μmol/L), OAT3, OCT1, OCT2, OATP1B1 (IC50 value of 14.4 μmol/L), OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.

Effects of Other Drugs on DXd: DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1 and BCRP.

12.4     Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of ENHERTU or of other anti-HER2 products.

During the median 11 to 18-month treatment period in patient with HER2-positive breast cancer patients in DESTINY-Breast03 and DESTINY-Breast02 with a median ADA sampling period of 13 to 20 months, the ADA incidence is 2.4% (16/658 patients) with 13% (2/16) patients tested positive for t neutralizing antibodies against fam-trastuzumab deruxtecan-nxki.


During the median 8-month treatment period in HER2-low breast cancer patients in DESTINY-Breast04 with a median ADA sampling period of 8 months, the ADA incidence is 2.0% (7/357 patients) with 0% (0/7) patients tested positive for neutralizing antibodies against fam-trastuzumab deruxtecan-nxki.

During the median 3.5-month treatment period in HER2-mutant NSCLC patients in DESTINY-Lung02 with a median ADA sampling period of 2.2 months, the ADA incidence is 0.7% (1/143 patients) with 0% (0/1) patients tested positive for neutralizing antibodies against fam-trastuzumab deruxtecan-nxki.

During the median 4.6-month treatment period in HER2-positive gastric or GEJ adenocarcinoma patients in DESTINY-Gastric01 with a median ADA sampling period of 4.6 months, the ADA incidence is 7.3%(9/123 of patients) with 0% (0/9) patients tested positive forneutralizing antibodies against fam- trastuzumab deruxtecan- nxki.

Because of the low occurrence of ADA, the effect of ADAs on the pharmacokinetics, pharmacodynamics, safety and/or effectiveness of fam- trastuzumab deruxtecan-nxki is unknown.