Drug Interaction Report

MONITOR: Coadministration with sotorasib may alter the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme as well as the P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) membrane transporters. Sotorasib may increase clearance via induction of CYP450 3A4, resulting in decreased plasma concentrations of substrates that are metabolized by the isoenzyme. However, sotorasib may also increase systemic bioavailability of P-gp and BCRP substrates via inhibition of transporter-mediated efflux in the intestine and possibly other organs such as the liver and kidney. When midazolam, a sensitive CYP450 3A4 substrate, was coadministered with sotorasib, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 48% and 53%, respectively. These results suggest moderate induction of CYP450 3A4 by sotorasib. On the contrary, coadministration of digoxin, a P-gp substrate, with sotorasib increased digoxin Cmax by 91% and AUC by 21%. Coadministration of rosuvastatin, a BCRP substrate, with sotorasib increased rosuvastatin Cmax by 70% and AUC by 34%. The P-gp and BCRP inhibiting effects of sotorasib may be most prominent with orally administered drugs. No formal studies have been conducted to evaluate the net pharmacokinetic effect on drugs that are substrates of CYP450 3A4 as well as P-gp and/or BCRP.

MANAGEMENT: Caution is advised when sotorasib is used concomitantly with drugs that are substrates of CYP450 3A4 as well as P-gp and/or BCRP, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information recommends avoiding coadministration of sotorasib with CYP450 3A4, P-gp, and/or BCRP substrates for which minimal concentration changes may lead to therapeutic failure or serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever sotorasib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a moderate CYP450 3A4 inducer and P-gp/BCRP inhibitor like sotorasib and for any dosage adjustments that may be required.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of lurasidone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single 10 mg dose of lurasidone was administered with the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 5 days), lurasidone peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 6.9- and 9.0-fold, respectively, compared to administration alone. The AUC of lurasidone's active metabolite increased by 6-fold. Another potent CYP450 3A4 inhibitor, posaconazole, has been reported to increase lurasidone AUC by approximately 4.5-fold. When a single 20 mg dose of lurasidone was administered with the moderate CYP450 3A4 inhibitor diltiazem (extended release formulation 240 mg/day for 5 days), lurasidone Cmax and AUC increased by 2.1- and 2.2-fold, respectively, while the AUC of the active metabolite increased by 2.4-fold. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

GENERALLY AVOID: Alcohol may potentiate some of the central nervous system and hypotensive effects of lurasidone. Use in combination may result in increased sedation, dizziness, hypotension, and impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of lurasidone. According to the product labeling, lurasidone mean Cmax and AUC were increased approximately 3-fold and 2-fold, respectively, when administered with food relative to under fasting conditions. Lurasidone AUC was not affected by meal size (in the range of 350 to 1000 calories) or fat content. In clinical studies, lurasidone was administered with food.

MANAGEMENT: Patients treated with lurasidone should avoid consumption of grapefruit and grapefruit juice as well as alcohol. Lurasidone should be taken with food (at least 350 calories).

Food does not appear to have a clinically significant effect on the oral bioavailability of sotorasib. When a 960 mg dose of sotorasib was administered to study patients with a high-fat, high-calorie meal (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), sotorasib peak plasma concentration (Cmax) did not change while systemic exposure (AUC 0-24 hours) increased by 25% compared to administration under fasted conditions. Sotorasib can be administered with or without food at approximately the same time each day.