Chemical formula: C₃₂H₃₅ClFN₇O₂ Molecular mass: 604.119 g/mol PubChem compound: 138611145
Adagrasib is a selective, irreversible inhibitor of KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive, GDP-bound conformation, which prevents KRAS-dependent downstream signalling. Adagrasib inhibits tumour cell growth and viability in cells harbouring KRAS G12C mutations and results in regression in KRAS G12C-positive nonclinical tumour models with minimal off-target activity.
Based on the concentration-QTcF relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 17.93 ms (15.13–20.73 ms) at the population geometric mean steady-state maximum concentration (Cmax,ss) in patients after administration of adagrasib 600 mg twice daily.
The pharmacokinetics of adagrasib have been characterised in healthy subjects and in patients with KRAS G12C-mutation. Adagrasib AUC and Cmax increase dose proportionally over the dose range of 400 mg to 600 mg. With a 600 mg twice daily dosing regimen in patients, adagrasib steady state was reached within 8 days of dosing, and adagrasib accumulated approximately 6-fold relative to a single dose.
The absolute oral bioavailability of adagrasib is unknown. The median Tmax of adagrasib is approximately 6 hours.
No clinically significant differences in the pharmacokinetics of adagrasib were observed following administration of a high-fat and high-calorie meal.
The geometric mean (CV%) apparent volume of distribution of adagrasib (Vz/F) in healthy subjects is 942 L (57%). Human plasma protein binding of adagrasib is approximately 99%.
Based on a population PK analysis, the estimated terminal elimination half-life (t1/2) and apparent oral clearance (CL/F) at steady state in patients are approximately 29 hours and 25.8 L/h, respectively.
Adagrasib is metabolised primarily by CYP3A4 and inhibits its own CYP3A4 metabolism.
Following a single oral dose of radiolabelled adagrasib, approximately 75% of the dose was recovered in faeces and 4.5% recovered in urine.
Based on a population pharmacokinetic analysis, no clinically meaningful differences in the pharmacokinetics of adagrasib were observed based on age (19 to 89 years), sex, race (White, Black and Asian), body weight (36 to 139 kg), ECOG PS (0, 1), or tumour burden. No clinically significant differences in the pharmacokinetics of adagrasib are expected in patients with mild to severe renal impairment (CLcr 15 to <90 mL/min estimated by Cockcroft-Gault equation) or in patients with mild to severe hepatic impairment (Child-Pugh classes A to C).
In repeat dose non-clinical safety studies with adagrasib, early deaths occurred in rats at dose ≥300 mg/kg/day (human equivalent dose of 2 900 mg/day). In animals that survived, the primary finding in rats and dogs was reversible phospholipidosis in multiple organs. In the rat, the target tissues included lung, trachea, heart, skeletal muscle, bone marrow, spleen, pancreas and female sex organs. In the dog, target tissues included bone marrow, lung, heart and spleen. The extent of vacuolation and the presence of foamy macrophages were more prominent in the rat as compared to dog, and these effects occurred at systemic exposures (based on AUC) below those in humans administered adagrasib at 600 mg twice daily in both species. The no observed adverse effect level in the 13-week rat and dog study was 150 mg/kg/day (human equivalent dose of 1 450 mg/day) and 15 mg/kg (human equivalent dose of 600 mg/day), respectively.
Adagrasib was not mutagenic or genotoxic in a battery of in vitro and in vivo assays. Carcinogenicity studies have not been conducted with adagrasib.
Dedicated fertility studies with adagrasib have not been conducted in animals. In the general toxicology studies conducted in rats and dogs, there was evidence of vacuolation in female sex organs that was suggestive of phospholipidosis, which reversed after cessation of dosing and was not considered adverse.
Adagrasib administration to pregnant rats at doses up to 270 mg/kg/day (human equivalent dose of 2 600 mg/day) during periods of organogenesis led to maternal toxicities, however at 90 mg/kg/day (human equivalent dose of 870 mg/day) there were no adverse effects on maternal or foetal development. In rabbits, at doses of 30 mg/kg/day (human equivalent dose of 580 mg/day) there were no adverse effects on dams and foetuses. Higher doses in rabbits led to maternal toxicities and embryofoetal lethality. In both the rat and rabbit studies, the exposures associated with no adverse effect dose levels were lower (less than 1-fold) compared to those obtained in humans at the clinical dose of 600 mg twice daily.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
