Molecular mass: 973.556 g/mol
Trastuzumab emtansine is a HER2-targeted antibody-drug conjugate which contains the humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.
Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumour cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).
Trastuzumab emtansine has the mechanisms of action of both trastuzumab and DM1:
The population pharmacokinetic analysis suggested no difference in trastuzumab emtansine exposure based on disease status (adjuvant vs. metastatic setting).
Trastuzumab emtansine is administered intravenously. There have been no studies performed with other routes of administration.
Patients in Study TDM4370g/BO21977 and Study BO29738 who received 3.6 mg/kg of trastuzumab emtansine intravenously every 3 weeks had a mean Cycle 1 maximum serum concentration (Cmax) of trastuzumab emtansine of 83.4 (± 16.5) μg/mL and 72.6 (± 24.3) μg/mL, respectively. Based on population PK analysis, following intravenous administration, the central volume of distribution of trastuzumab emtansine was (3.13 L) and approximated that of plasma volume.
Trastuzumab emtansine is expected to undergo deconjugation and catabolism by means of proteolysis in cellular lysosomes.
In vitro metabolism studies in human liver microsomes suggest that DM1, a small molecule component of trastuzumab emtansine, is metabolised mainly by CYP3A4 and to a lesser extent by CYP3A5. DM1 did not inhibit major CYP450 enzymes in vitro. In human plasma, trastuzumab emtansine catabolites MCC-DM1, Lys-MCC-DM1, and DM1 were detected at low levels. In vitro, DM1 was a substrate of P-glycoprotein (P-gp).
Based on population pharmacokinetic (PK) analysis, following intravenous administration of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, the clearance of trastuzumab emtansine was 0.68 L/day and the elimination half-life (t½) was approximately 4 days. No accumulation of trastuzumab emtansine was observed after repeated dosing of intravenous infusion every 3 weeks.
Based on population PK analysis, body weight, albumin, sum of longest diameter of target lesions by Response Evaluation Criteria In Solid Tumors (RECIST), HER2 shed extracellular domain (ECD), baseline trastuzumab concentrations, and aspartate aminotransferase (AST) were identified as statistically significant covariates for trastuzumab emtansine PK parameters. However, the magnitude of effect of these covariates on trastuzumab emtansine exposure suggests that these covariates are unlikely to have any clinically meaningful effect on trastuzumab emtansine exposure. In addition, exploratory analysis showed that the impact of covariates (i.e., renal function, race and age) on the pharmacokinetics of total trastuzumab and DM1 was limited and was not clinically relevant. In nonclinical studies, trastuzumab emtansine catabolites including DM1, Lys-MCC-DM1, and MCC-DM1 are mainly excreted in the bile with minimal elimination in urine.
Trastuzumab emtansine when administered intravenously every 3 weeks exhibited linear PK across doses ranging from 2.4 to 4.8 mg/kg; patients who received doses less than or equal to 1.2 mg/kg had faster clearance.
The population PK analysis showed that age did not affect the PK of trastuzumab emtansine. No significant difference was observed in the PK of trastuzumab emtansine among patients <65 years (n=577), patients between 65-75 years (n=78) and patients >75 years (n=16).
No formal PK study has been conducted in patients with renal impairment. The population PK analysis showed that creatinine clearance does not affect the PK of trastuzumab emtansine. Pharmacokinetics of trastuzumab emtansine in patients with mild (creatinine clearance CLcr 60 to 89 mL/min, n=254) or moderate (CLcr 30 to 59 mL/min, n=53) renal impairment were similar to those in patients with normal renal function (CLcr ≥90 mL/min, n=361). Pharmacokinetic data in patients with severe renal impairment (CLcr 15 to 29 mL/min) are limited (n=1), therefore no dosage recommendations can be made.
The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. The pharmacokinetics of trastuzumab emtansine and DM1-containing catabolites were evaluated after the administration of 3.6 mg/kg of trastuzumab emtansine to metastatic HER2+ breast cancer patients with normal hepatic function (n=10), mild (Child-Pugh A; n=10) and moderate (Child-Pugh B; n=8) hepatic impairment.
Plasma concentrations of DM1 and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1) were low and comparable between patients with and without hepatic impairment.
Systemic exposures (AUC) of trastuzumab emtansine at Cycle 1 in patients with mild and moderate hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic function, respectively. Trastuzumab emtansine exposure (AUC) at Cycle 3 after repeated dosing in patients with mild or moderate hepatic dysfunction was within the range observed in patients with normal hepatic function.
No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with severe hepatic impairment (Child-Pugh class C).
The population PK analysis showed that race did not appear to influence the PK of trastuzumab emtansine. Because most of the patients in trastuzumab emtansine clinical studies were females, the effect of gender on the PK of trastuzumab emtansine was not formally evaluated.
Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 10 mg/kg, respectively, corresponding to 2040 μg DM1/m² in both species, which is approximately equivalent to the clinical dose of trastuzumab emtansine in patients. In the GLP toxicity studies, with the exception of irreversible peripheral axonal toxicity (observed only in monkeys at ≥10 mg/kg) and reproductive organ toxicity (observed only in rats at 60 mg/kg), partially or completely reversible dose dependent toxicities were identified in both animal models. Principal toxicities included liver (liver enzyme elevations) at ≥20 mg/kg and ≥10 mg/kg, bone marrow (reduced platelet and white blood cell count)/hematologic at ≥20 mg/kg and ≥10 mg/kg, and lymphoid organs at ≥20 mg/kg and ≥3 mg/kg, in rat and monkey, respectively.
DM1 was aneugenic or clastogenic in an in vivo single-dose rat bone marrow micronucleus assay at exposures that were comparable to mean maximum concentrations of DM1 measured in humans administered trastuzumab emtansine. DM1 was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.
No fertility studies in animals have been performed to evaluate the effect of trastuzumab emtansine. However, based on results from general animal toxicity studies, adverse effects on fertility can be expected.
Dedicated embryo-foetal development studies have not been conducted in animals with trastuzumab emtansine. Developmental toxicity of trastuzumab has been identified in the clinical setting although it was not predicted in the non-clinical program. In addition, developmental toxicity of maytansine has been identified in non-clinical studies which suggests that DM1, the microtubule-inhibiting cytotoxic maytansinoid component of trastuzumab emtansine, will be similarly teratogenic and potentially embryotoxic.
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