Drug Interaction Report

MONITOR: Givinostat may increase the concentration of CYP450 3A4 substrates via inhibition of the isoenzyme. Givinostat appears to be a weak inhibitor of intestinal CYP450 3A4, but not a significant inhibitor or inducer of hepatic CYP450 3A4; hence, the interaction may be more significant for orally administered CYP450 3A4 substrates. A pharmacokinetic study conducted in healthy volunteers (n=26) found that the peak plasma concentration (Cmax) and systemic exposure (AUC) of a single dose of oral midazolam (2.5 mg) increased from baseline after 3 days of givinostat oral suspension (50 mg twice daily) by 24% and 39%, respectively. After 14 days of coadministration, the Cmax and AUC of oral midazolam had increased by 39% and 67%, respectively. When oral givinostat was studied in combination with intravenous midazolam, only a very slight increase in midazolam's AUC was observed.

MANAGEMENT: Caution and clinical monitoring are advised if givinostat is used in combination with an orally administered CYP450 3A4 sensitive substrate for which a small change in substrate plasma concentration could lead to serious toxicities. The labeling of the substrate should be consulted for specific monitoring, dose adjustment, and discontinuation recommendations should adverse reactions result from this combination.

ADJUST DOSING INTERVAL: Food increases the systemic exposure of givinostat. An open-label, randomized, crossover, single dose food effect study conducted in 12 healthy males used givinostat liquid filled capsules. Subjects received a single oral dose of givinostat (100 mg) in the fasting state or after a high-fat standard meal, with a washout period of at least 1 week in between. The high-fat standard meal resulted in an increase in systemic exposure (AUC) and maximum plasma concentration (Cmax) of about 40% and 23%, respectively, when compared to the fasted state. Additionally, the time to maximum concentration (Tmax) was delayed slightly from 2 to 3 hours.

MANAGEMENT: Givinostat should be administered with food to increase its absorption. In the case of the oral suspension, this can also help mask its bitter taste.