Drug Interactions between lopinavir / ritonavir and relugolix

GENERALLY AVOID: Coadministration with inhibitors of the P-glycoprotein (P-gp) efflux transporter may increase the plasma concentrations of relugolix, particularly when the inhibitors are given orally. Relugolix is a substrate for intestinal P-gp. In vitro, it is metabolized primarily by CYP450 3A and, to a lesser extent, by CYP450 2C8. When relugolix was coadministered with erythromycin, a combined P-gp and moderate CYP450 3A inhibitor, relugolix peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 6.2-fold. Increased exposure to relugolix may increase the risk and/or severity of adverse effects such as hot flushes; weight gain; decreased sex drive; erectile function difficulties; QT interval prolongation; musculoskeletal pain; constipation; diarrhea; increases in glucose, triglyceride, and liver transaminase levels; and decreased hemoglobin. No clinically significant differences in the pharmacokinetics of relugolix were observed when coadministered with voriconazole, a strong CYP450 3A inhibitor that does not inhibit P-gp.

MANAGEMENT: Concomitant use of relugolix with orally administered P-gp inhibitors should generally be avoided. If coadministration is required, the manufacturer recommends taking relugolix first and separating the dosing by at least 6 hours. Patients should be monitored more frequently for adverse effects. Alternatively, when relugolix is used as monotherapy for the treatment of prostate cancer, the prescribing information states that treatment with relugolix may be interrupted for up to two weeks if a short course of treatment with a P-gp inhibitor is necessary. Following interruption of relugolix for more than 7 days, the manufacturer recommends restarting therapy with a loading dose of 360 mg on the first day, then continuing with a dose of 120 mg once daily.

GENERALLY AVOID: Long-term androgen deprivation therapy (ADT) can prolong the QT interval. Coadministration of ADT with other agents that may prolong the QT interval could also result in additive effects and an increased risk of ventricular arrhythmias including torsade de pointes and sudden death. The risk may be increased in patients with certain underlying risk factors like congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Studies in young men have shown that endogenous serum testosterone levels are inversely associated with QTc (QT interval corrected for heart rate) duration. Clinical trials in men with low serum testosterone levels have reported testosterone administration being associated with a shortening of QTc. Likewise, studies using ADT have shown that it may prolong the QT interval; however, this effect may vary by drug, dose, or even each drug class that can be used to reduce testosterone levels. A clinical study comparing abarelix to a luteinizing hormone-releasing hormone agonist plus nonsteroidal antiandrogen therapy found that both therapies prolonged the mean Fridericia-corrected QT interval (QTcF) by more than 10 msec from baseline. Approximately 20% of patients in both groups had either changes from baseline QTc of >30 msec or end-of-treatment QTc values >450 msec. Similarly, a study comparing degarelix to leuprolide found that approximately 20% of patients on each drug had QT/QTc intervals >450 msec after 1 year of treatment. From baseline to end of study, the median change in QTcF was 12.3 msec for degarelix and 16.7 msec for leuprolide. Some drugs used to lower testosterone levels may also have other side effects that can predispose a patient to QT prolongation and torsade de pointes. For example, inhibitors of 17 alpha-hydroxylase/C17,20-lyase (CYP17) like abiraterone may cause hypokalemia as a result of increased mineralocorticoid levels. Clinical data on ADT prolonging the QT interval in women and children are lacking.

MANAGEMENT: The benefits of androgen deprivation therapy (ADT) should be carefully assessed against the potential risk in patients receiving other drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected prior to initiating therapy, and monitoring of electrocardiograms and electrolytes may be advisable. The manufacturer's labeling as well as current clinical guidelines should be consulted for monitoring recommendations.