Drug Interactions between osilodrostat and Yosprala

MONITOR: Coadministration with osilodrostat may increase the plasma concentrations of drugs that are metabolized by CYP450 1A2, 2C19, 2D6, and/or 3A4. Osilodrostat has been shown to be a moderate inhibitor of CYP450 1A2, a mild to borderline moderate inhibitor of CYP450 2C19, and a weak inhibitor of CYP450 2D6 and 3A4. In a pharmacokinetic study with 20 healthy volunteers using a single 50 mg dose of osilodrostat and a probe drug cocktail, osilodrostat increased the exposures to caffeine (CYP450 1A2 substrate), omeprazole (CYP450 2C19 substrate), dextromethorphan (CYP450 2D6 substrate), and midazolam (CYP450 3A4/5 substrate) by 2.5-, 1.9-, 1.5- and 1.5-fold, respectively.

MANAGEMENT: Caution is advised when osilodrostat is used concurrently with drugs that are substrates of CYP450 1A2, 2C19, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever osilodrostat is added to or withdrawn from therapy.

Coadministration with proton pump inhibitors may decrease the oral bioavailability of aspirin and other salicylates. The interaction has been studied with omeprazole and aspirin, although data are conflicting. In one study, pretreatment with omeprazole (20 mg/day for 2 days) in 11 healthy volunteers led to a significant and progressively greater reduction in the mean serum salicylate level at 30, 60, and 90 minutes after administration of aspirin (650 mg single dose). The investigators suggest that acid suppression may reduce the lipophilic nature of aspirin, thereby adversely affecting its absorption from the gastrointestinal tract. Another study found no effect of omeprazole pretreatment (20 mg/day for 4 days) on plasma salicylate and aspirin levels, skin bleeding times, or antiplatelet effect of low-dose aspirin (125 mg single dose) in 14 healthy volunteers. However, these results do not exclude the possibility that omeprazole might interfere with the analgesic, antipyretic, or anti-inflammatory effects of aspirin, which has been demonstrated in rats.

Proton pump inhibitors may enhance the release rate of salicylates from enteric-coated formulations due to premature disruption of the coating and intragastric release of the drug secondary to an increase in gastric pH. In eight healthy volunteers, omeprazole pretreatment (20 mg/day for 4 days) did not affect the bioavailability of salicylate from uncoated aspirin tablets but significantly increased the absorption rate of salicylate from enteric-coated sodium salicylate tablets. The clinical significance of this interaction is unknown. Theoretically, it may increase the risk of gastric adverse effects associated with salicylates.