Drug Interactions between lopinavir / ritonavir and siponimod

GENERALLY AVOID: Coadministration with drugs that cause moderate inhibition of CYP450 2C9 and moderate or strong inhibition of CYP450 3A4 may increase the plasma concentrations of siponimod, which is primarily metabolized by these isoenzymes. This interaction includes concomitant use of siponimod with a moderate CYP450 2C9/3A4 dual inhibitor or a moderate CYP450 2C9 inhibitor in combination with a separate moderate or strong CYP450 3A4 inhibitor. In healthy CYP450 2C9*1/*1 genotype volunteers, coadministration of a moderate CYP450 2C9/3A4 dual inhibitor (fluconazole 200 mg daily at steady-state) and siponimod (a single 4 mg dose) resulted in 2-fold and 50% increases in siponimod AUC and terminal half-life, respectively. According to in silico (computer-based) evaluation, use of fluconazole resulted in a 2- to 4-fold increase in the steady-state AUC of siponimod across different CYP450 2C9 genotypes. The CYP450 2C9 genotype influences the fractional contributions of CYP450 2C9 and 3A4 to overall elimination. If the metabolic activity of CYP450 2C9 is decreased, a larger contribution of CYP450 3A4 can be anticipated.

MANAGEMENT: Concomitant use of siponimod with a moderate or strong CYP450 2C9/3A4 dual inhibitor (e.g., fluconazole, mifepristone) or a moderate CYP450 2C9 inhibitor (e.g., abiraterone, amiodarone, fenofibrate, gemfibrozil, nitisinone, oxandrolone) in combination with a moderate or strong CYP450 3A4 inhibitor (e.g., amprenavir, aprepitant, atazanavir, boceprevir, ceritinib, chloramphenicol, ciprofloxacin, clarithromycin, cobicistat, conivaptan, crizotinib, dalfopristin-quinupristin, darunavir, delavirdine, diltiazem, dronedarone, erythromycin, fedratinib, fluvoxamine, fosamprenavir, fosaprepitant, fosnetupitant, fusidic acid, idelalisib, imatinib, indinavir, isavuconazole, itraconazole, ketoconazole, letermovir, mibefradil, nefazodone, nelfinavir, netupitant, posaconazole, ribociclib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, troleandomycin, verapamil, voriconazole, voxelotor) is not recommended. Caution is advised if siponimod is used in combination with moderate CYP450 2C9 inhibitors.

GENERALLY AVOID: Due to its significant bradycardic effects, the risk of QT prolongation and torsade de pointes arrhythmia may be increased during initiation of siponimod treatment in patients receiving drugs that prolong the QT interval. Siponimod can cause a decrease in heart rate during initiation of therapy that is apparent within an hour of the first dose, and the day 1 decline is maximal at approximately 3 to 4 hours. The maximal decrease in heart rate from baseline was seen between day 5 and 6. After day 6, heart rate starts increasing and reaches placebo levels within 10 days after treatment initiation. The highest daily postdose-dose decrease in absolute hourly mean heart rate is observed on day 1, with a decrease of 5 to 6 bpm. Following day 1, decreases in heart rate are less pronounced. Heart rates below 40 bpm were rarely observed. In controlled clinical trials, bradycardia (including sinus bradycardia and decreased heart rate) occurred in 6% of siponimod-treated patients compared to 3% of patients receiving placebo. Initiation of siponimod treatment has also resulted in transient AV conduction delays. First-degree AV block (prolonged PR interval on ECG) occurred in 5.1% of siponimod-treated patients and 1.9% of patients receiving placebo. Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of siponimod initiation in less than 1.7% of patients. Bradycardia and conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours, but they occasionally required treatment with atropine. In a study evaluating the effect on QT interval of siponimod 2 or 10 mg at steady-state, siponimod treatment resulted in maximum prolongations of the QTc of 7.8 and 7.2 msec, respectively, with upper bounds of the 90% confidence interval of 9.93 and 9.72 msec, respectively. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Siponimod has not been studied in patients receiving drugs that can prolong the QT interval. Because bradycardia and AV block are recognized risk factors for QT prolongation and torsade de pointes arrhythmia, treatment with siponimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties. Advice from a cardiologist should be sought if treatment with siponimod is considered in patients on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes or drugs that slow heart rate or AV conduction.