Assessing the Potential Clinical Drug-Drug Interactions Between D-1553 (Garsorasib) and CYP450 Enzymes/Transporters...

This Phase I drug-drug interaction study in healthy Chinese male subjects evaluated: (1) the perpetrator effects of D-1553 (garsorasib) on cytochrome P450 enzymes (CYP3A4, CYP1A2), hepatic (OATP1B1/1B3), renal uptake transporters (OAT1/3), and efflux transporter P-glycoprotein (P-gp); and (2) the victim potential with itraconazole (200 mg daily) or omeprazole (20 mg daily).

The study comprised three cohorts. Cohort 1 received D-1553 tablets (400 mg twice daily) co-administered with a cocktail of probe substrates: midazolam, caffeine, rosuvastatin, furosemide, and digoxin. Cohort 2 received D-1553 co-administered with the strong CYP3A4 and P-gp inhibitor itraconazole. Cohort 3 received D-1553 co-administered with the proton-pump inhibitor omeprazole. A total of 45 healthy male subjects were enrolled in the study, and 44 subjects were included in the safety and pharmacokinetic (PK) analyses. Plasma concentrations of D-1553 and concomitant drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Tolerability was also evaluated.

In the substrate cocktail assessment, D-1553 significantly inhibited CYP3A4 (midazolam AUC ratio: 2.04) but not CYP1A2 (caffeine AUC ratio: 1.18), and reduced exposures of rosuvastatin and furosemide (AUC ratio: 0.59 and 0.41, respectively), likely via intestinal OATP2B1 inhibition. Meanwhile, no clinically relevant effect on P-gp was shown (digoxin AUC ratio: 1.19). Co-administration with itraconazole increased D-1553 exposure (AUC ratio: 1.46), whereas omeprazole decreased its exposure (AUC ratio: 0.85). All AEs were mild and no serious AEs were reported.

D-1553 acts as a moderate inhibitor of CYP3A4 and a weak inhibitor of P-gp, while reducing the absorption of specific transporter substrates, likely via intestinal OATP2B1. Co-administration with strong CYP3A4 inhibitors moderately increases D-1553 exposure, whereas acid-reducing agents like omeprazole have no clinically relevant effect. These findings provide a targeted scientific basis for guiding the clinical co-administration of D-1553 with concomitant medications.