Chemical formula: C₇₆H₁₀₄N₁₂O₂₄S Molecular mass: 1,600.701 g/mol
Sacituzumab govitecan binds to Trop-2-expressing cancer cells and is internalised with the subsequent release of SN-38 from a hydrolysable linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death.
The serum pharmacokinetics of sacituzumab govitecan and SN-38 were evaluated in the ASCENT study in a population of mTNBC patients who received sacituzumab govitecan as a single agent at a dose of 10 mg/kg body weight. The pharmacokinetic parameters of sacituzumab govitecan and free SN-38 are presented in the following table.
Summary of mean PK parameters (CV%) of sacituzumab govitecan and free SN-38:
| Sacituzumab govitecan | Free SN-38 | |
|---|---|---|
| Cmax [ng/mL] | 242 000 (22%) | 91 (65%) |
| AUC0-168 [ng*h/mL] | 5 560 000 (24%) | 2 730 (41%) |
Cmax: maximum serum concentration
AUC0-168: area under serum concentration curve through 168 hours
Based on population pharmacokinetic analyses, the steady state volume of distribution of sacituzumab govitecan was 3.58 L.
The median elimination half-life (t1/2) of sacituzumab govitecan and free SN-38 in patients with metastatic triple negative breast cancer was 23.4 and 17.6 hours, respectively. Based on population pharmacokinetic analyses, the clearance of sacituzumab govitecan is 0.128 L/h.
No metabolism studies with sacituzumab govitecan have been conducted. SN-38 (the small molecule moiety of sacituzumab govitecan) is metabolised via UGT1A1.
Pharmacokinetic analyses in patients treated with sacituzumab govitecan (n=789) did not identify an effect of age, race, and mild or moderate renal impairment on the pharmacokinetics of sacituzumab govitecan.
Renal elimination is known to contribute minimally to the excretion of SN-38, the small molecule moiety of sacituzumab govitecan. There are no data on the pharmacokinetics of sacituzumab govitecan in patients with severe renal impairment or end-stage renal disease (CrCl <15 mL/min).
The exposure of sacituzumab govitecan is similar in patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN, or bilirubin >1.0 to ≤1.5 ULN and AST of any level; n=257) to patients with normal hepatic function (bilirubin and AST ≤ ULN; n=526). Sacituzumab govitecan and free SN-38 exposures are unknown in patients with moderate or severe hepatic impairment.
SN-38 was clastogenic in an in vitro mammalian cell micronucleus test in Chinese hamster ovary cells and was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. In a repeat-dose toxicity study in cynomolgus monkeys, intravenous administration of sacituzumab govitecan resulted in endometrial atrophy, uterine hemorrhage, increased follicular atresia of the ovary, and atrophy of vaginal epithelial cells at doses ≥60 mg/kg (1.9 times the human recommended dose of 10 mg/kg based on body weight allometric scaling).
Non-clinical data for the novel excipient MES reveal no special hazard for humans based on conventional repeated dose toxicity and genotoxicity studies.
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