Drug Interactions between aspirin / omeprazole and larotrectinib

MONITOR: Coadministration with larotrectinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. In study subjects, coadministration of midazolam, a sensitive CYP450 3A4 substrate, with larotrectinib 100 mg twice daily increased midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.7-fold each compared to administration of midazolam alone. The Cmax and AUC of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased by 1.4-fold.

MANAGEMENT: Caution is advised when larotrectinib is used concomitantly with drugs that are substrates of CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever larotrectinib is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects. Some authorities recommend avoiding concomitant use of larotrectinib and sensitive CYP450 3A4 substrates or substrates with narrow therapeutic ranges. These drugs include, but are not limited to: alfentanil, cisapride, colchicine, cyclosporine, fentanyl, ivacaftor, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, quinidine, sildenafil, ergot derivatives, macrolide immunosuppressants, and vinca alkaloids.

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.