Drug Interactions between adagrasib and Biktarvy

MONITOR: Coadministration with adagrasib may increase the plasma concentrations of drugs that are metabolized by the CYP450 3A4, 2D6 or 2C9 enzymatic pathways or are substrates of the P-glycoprotein (P-gp) efflux membrane transporter. When adagrasib 400 mg twice daily (two-thirds the approved recommended dosage) was administered with midazolam (a sensitive CYP450 3A4 substrate) and dextromethorphan (a sensitive CYP450 2D6 substrate) in pharmacokinetic studies, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.8- and 21-fold, respectively, while dextromethorphan Cmax and AUC increased by 1.9- and 1.8-fold, respectively. Adagrasib at the approved recommended dosage of 600 mg twice daily is predicted to increase midazolam Cmax by 3.1-fold and AUC by 31-fold; dextromethorphan Cmax by 1.7-fold and AUC by 2.4-fold; warfarin (a sensitive CYP450 2C9 substrate) Cmax by 1.1-fold and AUC by 2.9-fold; and digoxin (a P-gp substrate) Cmax by 1.9-fold and AUC by 1.5-fold. These results suggest that adagrasib is a potent inhibitor of CYP450 3A4 and may be a moderate inhibitor of CYP450 2D6 and 2C9 at the approved recommended dosage of 600 mg twice daily.

MANAGEMENT: Caution is advised when adagrasib is used concomitantly with drugs that are substrates of CYP450 3A4, CYP450 2D6, CYP450 2C9 and/or P-gp, particularly sensitive substrates or those with a narrow therapeutic range. Substitution for these medications is recommended when possible, or initiate with lower dosages and monitor patient clinical response/tolerance and titrate accordingly if coadministration is required. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or uridine diphosphate glucuronosyltransferase (UGT) 1A1 may increase the plasma concentrations of bictegravir. According to the product labeling, bictegravir is a substrate of both CYP450 3A4 and UGT1A1; however, the extent to which each enzymatic pathway contributes to the metabolic clearance of bictegravir has not been reported. In healthy volunteers studied under fasted conditions, administration of a single 75 mg dose of bictegravir during treatment with the potent CYP450 3A4 inhibitor voriconazole (300 mg twice daily) increased mean bictegravir peak plasma concentration (Cmax) and systemic exposure (AUC) by 9% and 61%, respectively, compared to administration of bictegravir alone. In addition, in healthy volunteers studied under fed conditions, administration of a single 75 mg dose of bictegravir during treatment with the potent CYP450 3A4 and UGT1A1 inhibitor atazanavir (400 mg once daily) increased mean bictegravir AUC by 315%, compared to administration of bictegravir alone.

MANAGEMENT: Caution is advised when bictegravir is used with CYP450 3A4 and UGT1A1 inhibitors. Patients should be monitored for increased adverse effects such as diarrhea, nausea, and vomiting.