Drug Interaction Report

MONITOR: Lazertinib may increase the concentration and adverse effects of drugs which rely on CYP450 3A4 and/or breast cancer resistance protein (BCRP) for clearance via inhibition of the isoenzyme and/or the efflux transporter. However, for drugs whose therapeutic effects are dependent on the formation of active metabolites via CYP450 3A4 (e.g., amiodarone, cyclophosphamide, ifosfamide), inhibition of this isoenzyme may result in a reduction in efficacy. In one pharmacokinetic study, healthy participants (n=20) received the sensitive CYP450 3A4 substrate midazolam and BCRP substrate rosuvastatin at baseline and again with steady-state lazertinib. Coadministration increased midazolam's peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.4- and 1.5-fold, respectively. Likewise, rosuvastatin's Cmax and AUC increased by 2.2- and 2-fold, respectively. Data for less sensitive substrates or drugs metabolized and/or transported by multiple routes are unavailable.

MANAGEMENT: Caution is advised if lazertinib is used concurrently with agents that are substrates of CYP450 3A4 and/or the efflux transporter BCRP. This may be particularly important in cases where minimal changes in the substrate's concentration could result in serious adverse reactions (if the agent is cleared via CYP450 3A4 and/or BCRP) or a significant reduction in efficacy (if the medication has active metabolites formed via CYP450 3A4). Dose adjustments and/or increased monitoring may be required. Consultation with the labeling of the substrate in question is advised.

ADJUST DOSING INTERVAL: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of rimegepant. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Concomitant administration of a single dose of rimegepant (75 mg) with itraconazole, a strong CYP450 3A4 inhibitor, at steady state increased the systemic exposure (AUC) and peak plasma concentration (Cmax) of rimegepant by 4-fold and approximately 1.5-fold, respectively. The manufacturer also states that concomitant administration of rimegepant with a moderate CYP450 3A4 inhibitor may increase rimegepant AUC by less than 2-fold. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MONITOR: When administered with a high-fat meal under fed condition, Tmax was delayed by 1 hour, which resulted in a 42% to 53% reduction in Cmax and a 32% to 38% reduction in AUC. However, the impact of this reduction on rimegepant efficacy remains unknown.

MANAGEMENT: Rimegepant may be administered with or without food. Until more information is available, patients receiving rimegepant may want to avoid the regular consumption of grapefruits and grapefruit juice to prevent undue increases in plasma levels and systemic effects of rimegepant. If grapefruit or grapefruit juice is consumed concomitantly with rimegepant, the manufacturer recommends avoiding another dose of rimegepant within 48 hours.