Chemical formula: C₃₀H₃₀F₂N₆O₃ Molecular mass: 560.606 g/mol
Sotorasib is a selective KRAS G12C (Kirsten rat sarcoma viral oncogene homolog) inhibitor, which covalently and irreversibly binds to the unique cysteine of KRAS G12C. Inactivation of KRAS G12C by sotorasib blocks tumour cell signalling and survival, inhibits cell growth, and promotes apoptosis selectively in tumours harbouring KRAS G12C, an oncogenic driver of tumourigenesis.
Bioavailability of sotorasib has not been investigated in humans. Following an oral, single-dose administration, sotorasib was absorbed with median time to achieve peak concentration of 1 hour.
Following administration of sotorasib with a high-fat, high-calorie meal, there was no effect on Cmax, and AUC increased by 38% compared to administration under fasted conditions. Sotorasib can be administered with or without food.
The geometric mean apparent volume of distribution after 960 mg PO QD for 8 consecutive days of sotorasib was 211 L (determined using noncompartmental analysis). In vitro, plasma protein binding of sotorasib was 89% and sotorasib bound preferentially to alpha-1-acid glycoprotein in vitro.
The main metabolic pathways of sotorasib were non-enzymatic conjugation and oxidative metabolism. In vitro data indicate that sotorasib is metabolised by cytochrome P4502C8, CYP3A4, and CYP3A5, and is a substrate of P-glycoprotein (P-gp). Following single oral administration of a radioactive sotorasib dose of 720 mg, a cysteine adduct (formed through hydrolysis of a glutathione adduct) and an oxidative metabolite resulting from CYP3A-mediated cleavage of the piperazine acrylamide moiety were the primary circulating metabolites. Neither of these metabolites were pharmacologically active.
The geometric mean apparent clearance after 960 mg PO QD for 8 consecutive days of sotorasib was 26.2 L/hour (determined using noncompartmental analysis). The mean half-life is 5 hours. Steady state was reached within 22 days and remained stable. Sotorasib is primarily eliminated in faeces, with approximately 74% of the dose recovered in faeces and 6% (1% unchanged) recovered in urine.
Sotorasib exhibited nonlinear pharmacokinetics over a range of single and multiple oral administration doses studied between 180 to 960 mg QD as Cmax and AUC0-24 hour were less than dose proportional. The average Cmax and AUC0-24 hour values following multiple doses were similar for all dosing regimens from 180 mg QD to 960 mg QD. Exposure to sotorasib decreases over time following 960 mg QD dosing regimen until steady state is reached. Steady state plasma concentrations were achieved by approximately 3 weeks across the phase 1 and phase 2 clinical studies across all sotorasib doses.
Initial results of a population PK analysis suggests no clinically meaningful differences in the pharmacokinetics of sotorasib based on age, sex, race or ethnicity, body weight, line of therapy, ECOG PS, serum albumin, mild renal impairment (CrCL: ≥60 mL/min), or mild hepatic impairment (AST or ALT <2.5 × ULN or total bilirubin <1.5 × ULN). The effect of moderate to severe renal or hepatic impairment on sotorasib pharmacokinetics has not been studied.
Sotorasib was not mutagenic in a bacterial mutagenicity (Ames) assay. Sotorasib was not genotoxic in the in vivo rat micronucleus and comet assays.
Carcinogenicity studies have not been performed with sotorasib.
In rat and rabbit embryo-foetal development studies, oral sotorasib was not teratogenic.
In the rat, there were no effects on embryo-foetal development up to the highest dose tested (3.9 times higher than the exposure at the maximum recommended human dose [MRHD] of 960 mg based on area under the curve [AUC]).
In the rabbit, lower foetal body weights and a reduction in the number of ossified metacarpals in foetuses were observed only at the highest dose level tested (2.2 times higher than the exposure at the MRHD of 960 mg based on AUC), which was associated with maternal effects such as decreased body weight gain and food consumption during the dosing phase. Reduced ossification, as evidence of growth retardation associated with reduced foetal body weight, was interpreted as a non-specific effect in the presence of significant maternal toxicity.
Fertility/early embryonic development studies were not conducted with sotorasib. There were no adverse effects on male or female reproductive organs in general toxicology studies conducted in dogs and rats.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
Environmental risk assessment studies have shown that sotorasib has the potential to be very persistent to the environment. There is no potential for bioaccumulation or toxicity.
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