Datopotamab deruxtecan is a TROP2-directed antibody-drug conjugate. The antibody is a humanised anti-TROP2 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 antibody binds to TROP2 expressed on the surface of certain tumour cells. After binding, datopotamab deruxtecan undergoes internalisation into the tumour cells. Subsequently, the release of DXd results in DNA damage and apoptotic cell death via topoisomerase I inhibition. Datopotamab deruxtecan may also exhibit indirect cytotoxicity as shown in vitro through mechanisms of antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and bystander cytotoxicity of DXd against TROP2 expressing tumour cells and neighbouring cells.
As with all therapeutic proteins, there is a potential for immunogenicity. During the median 5.5 month treatment period across clinical studies in NSCLC and breast cancer patients treated with datopotamab deruxtecan at 6 mg/kg, the incidence of anti-datopotamab deruxtecan antibodies was 16% (146 out of 912) and the incidence of neutralising antibodies against datopotamab deruxtecan was 2.5% (23 out of 912). There was no apparent effect of anti-drug antibodies on the pharmacokinetics or effectiveness of datopotamab deruxtecan. No clinically meaningful impact on the safety of datopotamab deruxtecan was observed.
The pharmacokinetics of datopotamab deruxtecan was evaluated in 729 patients.
At the recommended dosage of datopotamab deruxtecan, the geometric mean (coefficient of variation [CV]%) Cmax of datopotamab deruxtecan and DXd were 154 μg/mL (20.3%) and 2.82 ng/mL (58.1%), respectively, and the AUC (area under the plasma concentration versus time curve) of datopotamab deruxtecan and DXd were 671 μg*day/mL (31.4%) and 18.5 ng*day/mL (42.6%) after the first dose in cycle 1, respectively.
Steady state volume of distribution of datopotamab deruxtecan is 3.52 L. In vitro, across the concentration range of 10 ng/mL to 100 ng/mL, the mean human plasma protein binding of DXd was 96.8 to 98.0%, and the blood-to-plasma concentration ratio of DXd was 0.59-0.62.
Datopotamab deruxtecan undergoes intracellular cleavage by lysosomal enzymes to release DXd. The humanised TROP2 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 primarily metabolised by CYP3A4 via oxidative pathways and does not undergo significant metabolism by UGT or other CYP enzymes.
Following intravenous administration of datopotamab deruxtecan in patients, the clearance of datopotamab deruxtecan was estimated to be 0.57 L/day. The median elimination half-life (t1/2) of datopotamab deruxtecan was 4.82 days and apparent median t1/2 of released DXd was approximately 5.50 days. In vitro, DXd was a substrate of P-gp, OATP1B1, OATP1B3, MATE2-K, MRP1 and BCRP. DXd excretion was not studied in humans.
In vitro studies indicate DXd does not inhibit or induce 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, OATP1B1 or BCRP transporters.
The exposure of datopotamab deruxtecan and released DXd when administered intravenously increased in proportion to dose in the 4 mg/kg to 10 mg/kg dose range (approximately 0.7 to 1.7 times the recommended dose). No accumulation of datopotamab deruxtecan was observed at the 6 mg/kg dose between cycle 1 and cycle 3.
Based on population pharmacokinetic analysis, age (26 to 86 years), race, region, and sex did not have a clinically meaningful effect on exposure of datopotamab deruxtecan or DXd. The mean volume of distribution and clearance of datopotamab deruxtecan and DXd increase with increasing body weight (35.6 kg to 156 kg). This is considered clinically relevant.
No dedicated renal impairment study was conducted. Based on population pharmacokinetic analysis including patients with mild to moderate (CLcr ≥30 and <90 mL/min) renal impairment (estimated by Cockcroft-Gault), the pharmacokinetics of datopotamab deruxtecan or DXd was not affected by mild to 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 including patients with mild hepatic impairment (total bilirubin ≤ ULN and any AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST), the pharmacokinetics of datopotamab deruxtecan or DXd was not affected by mild hepatic impairment as compared to normal hepatic function. There are limited data in patients with moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment to draw conclusions. Insufficient data are available for patients with severe (total bilirubin >3 times ULN and any AST) hepatic impairment. Therefore, patients with moderate and severe hepatic impairment should be monitored carefully.
In animals, toxicities were observed in lymphatic and haematopoietic organs, intestines, kidneys, male and female reproductive tracts, lung, skin, eye (cornea), liver and incisor teeth following the administration of datopotamab deruxtecan at exposure levels of the topoisomerase I inhibitor below clinical plasma exposure. In these animals, 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.
Carcinogenicity studies have not been conducted with datopotamab deruxtecan.
Dedicated fertility studies have not been conducted with datopotamab deruxtecan. Based on the results from an animal toxicity study in rats, datopotamab deruxtecan at 200 mg/kg (approximately 29 times the human recommended dose of 6 mg/kg based on AUC) may impair male and female reproductive function and fertility at exposure levels of the topoisomerase I inhibitor below clinical plasma exposure. Toxicity to male reproductive tract included testis (degeneration of germinal epithelium and atrophy of seminiferous tubule) and epididymis (single cell necrosis of ductal epithelium, cell debris in duct and decreased number of spermatozoa in duct), which did not reverse after 8 weeks of treatment cessation, except for single cell necrosis of ductal epithelium. The effects on female fertility, including an increase in the number of atretic follicles in the ovaries and single cell necrosis of mucosal epithelium in the vagina, may be reversible.
Reproductive and developmental toxicity studies have not been conducted with datopotamab deruxtecan. Based on results from general animal toxicity studies, datopotamab deruxtecan and DXd were toxic to rapidly dividing cells (testes), and DXd was genotoxic, suggesting the potential for embryotoxicity and teratogenicity.
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