Trastuzumab deruxtecan is a HER2-targeted antibody-drug conjugate. The antibody is a humanised anti-HER2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor (DXd) bound by a tetrapeptide-based cleavable linker. The antibody-drug conjugate is stable in plasma. The function of the antibody portion is to bind to HER2 expressed on the surface of certain tumour cells. After binding, the trastuzumab deruxtecan complex then undergoes internalisation and intracellular linker cleavage by lysosomal enzymes that are upregulated in cancer cells. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death. DXd, an exatecan derivative, is approximately 10 times more potent than SN-38, the active metabolite of irinotecan.
In vitro studies indicate that the antibody portion of trastuzumab deruxtecan, which has the same amino acid sequence as trastuzumab, also binds to FcγRIIIa and complement C1q. The antibody mediates antibody-dependent cellular cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2. In addition, the antibody inhibits signalling through the phosphatidylinositol 3-kinase (PI3-K) pathway in human breast cancer cells that overexpress HER2.
Trastuzumab deruxtecan is administered intravenously. There have been no studies performed with other routes of administration.
Based on population pharmacokinetic analysis, the volume of distribution of the central compartment (Vc) of trastuzumab deruxtecan and topoisomerase I inhibitor, DXd, were estimated to be 2.68 L and 28.0 L, respectively.
In vitro, the mean human plasma protein binding of DXd was approximately 97%.
In vitro, the blood to plasma concentration ratio of DXd was approximately 0.6.
Trastuzumab deruxtecan undergoes intracellular cleavage by lysosomal enzymes to release the DXd.
The humanised 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 metabolism studies in human liver microsomes indicate that DXd is metabolised mainly by CYP3A4 via oxidative pathways.
Following intravenous administration of trastuzumab deruxtecan in patients with metastatic HER2-positive, HER2-low breast cancer or HER2-mutant NSCLC, the clearance of trastuzumab deruxtecan in population pharmacokinetic analysis was calculated to be 0.4 L/day and the clearance of DXd was 18.4 L/h. In patients with locally advanced or metastatic gastric or GEJ adenocarcinoma, trastuzumab deruxtecan clearance was 20% higher than in patients with metastatic HER2-positive breast cancer. In cycle 3, the apparent elimination half-life (t1/2) of trastuzumab deruxtecan and released DXd was approximately 7 days. Moderate accumulation (approximately 35% in cycle 3 compared to cycle 1) of trastuzumab deruxtecan was observed.
Following intravenous administration of DXd to rats, the major excretion pathway was faeces via the biliary route. DXd was the most abundant component in urine, faeces, and bile. Following single intravenous administration of trastuzumab deruxtecan (6.4 mg/kg) to monkeys, unchanged released DXd was the most abundant component in urine and faeces. DXd excretion was not studied in humans.
In vitro studies indicate DXd does not inhibit major CYP450 enzymes including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A. In vitro studies indicate that DXd does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.
In vitro, DXd was a substrate of P-gp, OATP1B1, OATP1B3, MATE2-K, MRP1, and BCRP. No clinically meaningful interaction is expected with medicinal products that are inhibitors of MATE2-K, MRP1, P-gp, OATP1B, or BCRP transporters.
The exposure of trastuzumab deruxtecan and released DXd when administered intravenously increased in proportion to dose in the 3.2 mg/kg to 8.0 mg/kg dose range (approximately 0.6 to 1.5 times the recommended dose) with low to moderate inter-subject variability. Based on population pharmacokinetic analysis, inter-subject variability in trastuzumab deruxtecan and DXd elimination clearances were 24% and 28%, respectively, and for central volume of distribution were 16% and 55%, respectively. The intra-subject variability in trastuzumab deruxtecan and DXd AUC values (area under the serum concentration versus time curve) was approximately 8% and 14%, respectively.
Based on population pharmacokinetic analysis, age (20-96 years), race, ethnicity, sex and body weight did not have a clinically meaningful effect on exposure of trastuzumab deruxtecan or released DXd.
The population PK analysis showed that age (range: 20-96 years) did not affect the PK of trastuzumab deruxtecan.
No dedicated renal impairment study was conducted. Based on population pharmacokinetic analysis including patients with mild (creatinine clearance [CLcr] ≥60 and <90 mL/min) or moderate (CLcr ≥30 and <60 mL/min) renal impairment (estimated by Cockcroft-Gault), the pharmacokinetics of the released DXd was not affected by mild or moderate renal impairment as compared to normal renal function (CLcr ≥90 mL/min).
No dedicated hepatic impairment study was conducted. Based on population pharmacokinetic analysis, the impact of changes on pharmacokinetics of trastuzumab deruxtecan in patients with total bilirubin ≤1.5 times ULN, irrespective of AST level, is not clinically meaningful. There is limited data for patients with total bilirubin >1.5 to 3 times ULN, irrespective of AST level, to draw conclusions, and no data is available for patients with total bilirubin >3 times ULN, irrespective of AST level.
No studies have been conducted to investigate the pharmacokinetics of trastuzumab deruxtecan in children or adolescents.
In animals, toxicities were observed in lymphatic and haematopoietic organs, intestines, kidneys, lungs, testes and skin following the administration of trastuzumab deruxtecan at exposure levels of the topoisomerase I inhibitor (DXd) below clinical plasma exposure. In these animals, antibody-drug conjugate (ADC) exposure levels were similar or above clinical plasma exposure.
DXd was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.
Carcinogenicity studies have not been conducted with trastuzumab deruxtecan.
Dedicated fertility studies have not been conducted with trastuzumab deruxtecan. Based on results from general animal toxicity studies, trastuzumab deruxtecan may impair male reproductive function and fertility.
There were no animal reproductive or developmental toxicity studies conducted with trastuzumab deruxtecan. Based on results from general animal toxicity studies, trastuzumab deruxtecan and DXd were toxic to rapidly dividing cells (lymphatic/haematopoietic organs, intestine, or testes), and DXd was genotoxic, suggesting the potential for embryotoxicity and teratogenicity.
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