Drug Interactions between ivacaftor / lumacaftor and siponimod

GENERALLY AVOID: Coadministration with drugs that cause moderate induction of CYP450 2C9 and strong induction of CYP450 3A4 may decrease the plasma concentrations of siponimod, which is primarily metabolized by these isoenzymes. This interaction includes concomitant use of siponimod with a moderate CYP450 2C9/strong CYP450 3A4 dual inducer or a moderate CYP450 2C9 inducer in combination with a separate strong CYP450 3A4 inducer. In CYP450 2C9*1/*1 genotype subjects, coadministration of a moderate CYP450 2C9/strong CYP450 3A4 dual inducer (rifampin 600 mg daily) and siponimod (2 mg daily) resulted in 57% and 45% decreases in siponimod steady-state AUC and Cmax, respectively. According to in silico (computer-based) evaluation, use of rifampin and efavirenz (moderate CYP450 3A4 inducer) resulted in decreases up to 78% and up to 52%, respectively, of siponimod steady-state AUC across 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 and drugs that cause moderate induction of CYP450 2C9 and strong induction of CYP450 3A4 (e.g., carbamazepine, enzalutamide, rifampin) is not recommended for all patients. Concomitant use of siponimod and moderate or strong CYP450 3A4 inducers (e.g., apalutamide, bosentan, dabrafenib, dexamethasone, efavirenz, eslicarbazepine, etravirine, fosphenytoin, lorlatinib, lumacaftor, mitotane, modafinil, nafcillin, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, sotorasib, St. John's wort) is not recommended for patients with CYP450 2C9*1/*3 and *2/*3 genotypes.

MONITOR: Coadministration with ivacaftor or deutivacaftor may increase the plasma concentrations of drugs that are substrates of the CYP450 2C9 isoenzyme. The proposed mechanism, based on in vitro data, involves decreased metabolic clearance due to inhibition of CYP450 2C9 by ivacaftor and/or deutivacaftor. The clinical relevance is unknown.

MANAGEMENT: Caution is advised when ivacaftor or deutivacaftor containing medications are used concurrently with drugs that are known CYP450 2C9 substrates, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ivacaftor or deutivacaftor are added to or withdrawn from therapy.