Chemical formula: C₄₄H₅₈N₈O₅S Molecular mass: 810.425 g/mol PubChem compound: 164726578
Daraxonrasib is an inhibitor of the RAS GTPase family. Daraxonrasib binds to cyclophilin A, resulting in a binary complex that binds to the active, GTP-bound state of RAS. The tri-complex inhibits RAS signaling by blocking interactions with downstream effectors and promoting GTP hydrolysis to the inactive GDP-bound state of RAS. Daraxonrasib inhibition of wild-type and mutant variants of KRAS, NRAS, and HRAS induces tumor growth suppression and apoptosis. In RAS-dependent models of pancreatic adenocarcinoma, daraxonrasib treatment led to tumor growth inhibition and regression and is associated with antitumor immunity.
Daraxonrasib exposure-response relationships and time course of pharmacodynamic response have not been fully characterized.
Based on exposure and safety data from patients with pancreatic adenocarcinoma receiving 10 to 400 mg once daily of daraxonrasib (n=466), higher daraxonrasib exposure was associated with higher incidence of dose interruption/reduction/discontinuation, Grade ≥3 adverse reactions, Grade ≥2 dermatologic reactions, mucositis/stomatitis, nausea/vomiting, and diarrhea.
At the recommended dosage, a mean increase in the QTc interval >20 msec was not observed.
The pharmacokinetics of daraxonrasib were studied in healthy subjects and patients with advanced solid tumors, including patients with pancreatic adenocarcinoma treated with 300 mg once daily, and are presented as geometric mean (geometric percent coefficient of variation), unless otherwise specified.
Daraxonrasib maximum concentration is 365 ng/mL (50%) and total systemic exposure (AUC) is 3760 ng·h/mL (46%). Daraxonrasib AUC increases in an approximately dose proportional manner whereas Cmax increases in a less than dose proportional manner over the dose range of 80 mg (0.27 times the recommended dose) to 300 mg. Minimal to no accumulation was observed for AUC.
Daraxonrasib median (min, max) time to reach maximum concentration (Tmax) is approximately 2.2 hours (0.67, 8.0).
Effect of Food
No clinically significant differences in daraxonrasib pharmacokinetics were observed following administration of a high-fat, high-calorie meal (800 to 1000 calories, 50% from fat).
Daraxonrasib apparent (oral) volume of distribution during the terminal elimination phase is 1060 L (48%).
Daraxonrasib plasma protein binding is approximately 98% in vitro and is not concentration-dependent. Daraxonrasib blood to plasma ratio is concentration-dependent and ranges from 1.7 to 2.6 in healthy subjects.
Daraxonrasib mean (SD) terminal elimination half-life is 9.2 (±2.7) hours with an apparent (oral) clearance (CL/F) of 80.4 L/h (44%).
Daraxonrasib is primarily metabolized by CYP3A.
After a single oral dose of radiolabeled daraxonrasib 220 mg to healthy subjects, approximately 93% of the dose was recovered in feces (51% unchanged) and approximately 1% was recovered in urine (1% unchanged).
Specific Populations
No clinically significant differences in the pharmacokinetics of daraxonrasib were observed based on age (19 to 87 years old), sex, race (72% White, 11% Asian, 4% Black or African American), body weight (37 to 171 kg), ECOG PS (0, 1), tumor burden, CLcr 30 to 89 mL/min, or mild (total bilirubin > ULN to 1.5 × ULN or AST > ULN (with bilirubin normal)) or moderate (total bilirubin > 1.5 to 3 × ULN (with any AST level)) hepatic impairment per NCI-ODWG classification. The effects of CLcr < 30 mL/min or severe hepatic impairment (total bilirubin > 3 to 10 × ULN (with any AST level)) on daraxonrasib pharmacokinetics are unknown.
Strong CYP3A Inhibitors with P-gp Inhibition: Daraxonrasib AUC was observed to increase 5.1-fold following concomitant use of itraconazole 200 mg once daily (a strong CYP3A inhibitor with P-gp inhibition).
Strong CYP3A Inhibitors without P-gp Inhibition: Daraxonrasib AUC is predicted to increase 2.0-fold following concomitant use of voriconazole 200 mg twice daily (a strong CYP3A inhibitor without P-gp inhibition).
Moderate CYP3A Inhibitors with P-gp Inhibition: Daraxonrasib AUC is predicted to increase 2.6-fold following concomitant use of verapamil 80 mg three times daily (a moderate CYP3A inhibitor with P-gp inhibition).
Moderate CYP3A Inhibitors without P-gp Inhibition: Daraxonrasib AUC is predicted to increase 1.5-fold following concomitant use of fluconazole 200 mg once daily (a moderate CYP3A inhibitor without P-gp inhibition).
P-gp Inhibitors: Daraxonrasib AUC was observed to increase 1.8-fold following concomitant use of quinidine 300 mg three times daily (a P-gp inhibitor).
Strong CYP3A Inducers: Daraxonrasib AUC was observed to decrease to 50% following concomitant use of phenytoin 100 mg three times daily (a strong CYP3A inducer) and is predicted to decrease to 30% following concomitant use of rifampin 600 mg once daily (a strong CYP3A inducer).
Moderate CYP3A Inducers: Daraxonrasib AUC is predicted to decrease to 50% to 84% following concomitant use of efavirenz 600 mg once daily and modafinil 400 mg once daily (moderate CYP3A inducers).
P-gp Substrates: Free dabigatran Cmax and AUC are predicted to increase 2.5-fold and 2.1-fold, respectively, following concomitant use of daraxonrasib 300 mg once daily. No clinically significant differences in free dabigatran pharmacokinetics are predicted when daraxonrasib 300 mg once daily is given 4 hours apart from dabigatran etexilate.
Other Drugs: No clinically significant differences in daraxonrasib pharmacokinetics were observed when used concomitantly with esomeprazole (a proton pump inhibitor).
No clinically significant differences in the pharmacokinetics of the following drugs were observed or predicted when used concomitantly with daraxonrasib: midazolam (a sensitive CYP3A substrate), rosuvastatin (a BCRP/OATP1B3 substrate), and pravastatin (an OATP1B3 substrate).
In a 4-week toxicity study in mice, increased bone remodeling was observed at ≥ 10 mg/kg/day (exposures at or greater than the recommended dose based on AUC) and was partially reversible. The finding was characterized by increased number and size of osteoclasts (metaphyseal cut-back zone and diaphyseal periosteum) and structural bone changes (wider cortical walls, wider Haversian canals, larger osteocytes/lacunae).
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