Drug Interactions between lazertinib and sofosbuvir / velpatasvir / voxilaprevir

MONITOR: Coadministration with inhibitors of organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may increase the plasma concentrations of voxilaprevir, which is a substrate of the hepatic uptake transporters. When a single 100 mg dose of voxilaprevir was administered with a single 600 mg dose of the potent OATP 1B1/1B3 inhibitor cyclosporine (n=24), mean voxilaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 19.0- and 9.4-fold, respectively. Inhibition of P-glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-mediated intestinal transport and CYP450 3A4-mediated metabolism of voxilaprevir may also contribute to the overall interaction with cyclosporine. The safety of such high levels of voxilaprevir has not been established.

MANAGEMENT: Caution and monitoring are advised when voxilaprevir is used with OATP 1B1 or 1B3 inhibitors.

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.