Drug Interactions between lazertinib and macitentan / tadalafil

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of tadalafil, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of tadalafil should be considered.

MANAGEMENT: Caution is advised if tadalafil is prescribed with CYP450 3A4 inhibitors. Dosage adjustments may be appropriate for tadalafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. Tadalafil labeling recommends that the dosage not exceed 10 mg once every 72 hours in patients treated concomitantly with a potent CYP450 3A4 inhibitor, such as erythromycin, itraconazole, ketoconazole, protease inhibitors, and nefazodone. Patients should be advised to promptly notify their physician if they experience potential symptoms of PDE5 inhibitor toxicity such as pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

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.