Drug Interactions between ivacaftor / lumacaftor and lapatinib

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of lapatinib, which is primarily metabolized by the isoenzyme. In 24 healthy subjects, administration of a single 250 mg oral dose of lapatinib following treatment with the potent CYP450 3A4 inducer carbamazepine (100 mg twice daily for 3 days, then 200 mg twice daily for 17 days) decreased mean lapatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 59% and 72%, respectively, compared to administration of lapatinib alone. Reduced efficacy of lapatinib may occur.

MANAGEMENT: Concomitant use of lapatinib with potent CYP450 3A4 inducers should generally be avoided. If coadministration is required, a gradual dosage increase of lapatinib should be considered. The prescribing information recommends titrating the lapatinib dosage gradually from 1250 mg/day up to 4500 mg/day or from 1500 mg/day up to 5500 mg/day depending on the indication and patient tolerability. Based on pharmacokinetic studies, this dosage recommendation is predicted to adjust the lapatinib systemic exposure (AUC) to the range observed without inducers. However, clinical data are lacking. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The dosage of lapatinib should be reduced over approximately 2 weeks to the indicated dosage following discontinuation of the potent CYP450 3A4 inducer.

MONITOR: Coadministration with ivacaftor may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme and/or P-glycoprotein (P-gp) efflux transporter. The mechanism is decreased clearance via these pathways due to inhibition by ivacaftor and its pharmacologically active M1 metabolite. The interaction has been studied with midazolam and digoxin, probe substrates for CYP450 3A4 ad P-gp, respectively. In study subjects, midazolam systemic exposure (AUC) increased by 1.5-fold when it was administered with ivacaftor, suggesting weak inhibition of CYP450 3A4 by ivacaftor. Likewise, digoxin AUC increased by 1.3-fold with ivacaftor, which is also consistent with weak inhibition of P-gp by ivacaftor.

MANAGEMENT: Caution is advised when ivacaftor is used with drugs that are substrates of CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ivacaftor is added to or withdrawn from therapy.