Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of atrasentan, which is primarily metabolized by the isoenzyme. In drug interaction studies, coadministration with the potent CYP450 3A4 inducer rifampin reduced atrasentan (single dose, 10 mg) trough plasma concentration (Ctrough) by 90%. Rifampin is also an inhibitor of the hepatic influx transporters organic anion transporting polypeptides (OATP) 1B1 and 1B3, of which atrasentan is a substrate. No data are available about potent or moderate CYP450 3A4 inducers that do not inhibit OATP1B1 and/or 1B3, but greater decreases in atrasentan exposure may occur.

MANAGEMENT: Concomitant use of atrasentan with potent or moderate CYP450 3A4 inducers should generally be avoided.

ADJUST DOSING INTERVAL: Food increases the systemic exposure to both telotristat ethyl and its active metabolite, telotristat. Following administration of a single 500 mg dose of telotristat ethyl (twice the recommended dose) with a high-fat meal, telotristat ethyl peak plasma concentration (Cmax) and systemic exposure (AUC) were 112% and 264% higher, respectively, compared to administration under fasted conditions. The Cmax and AUC values for telotristat were also increased by 47% and 33%, respectively. The in vitro inhibitory potency of telotristat towards tryptophan hydroxylase has been shown to be approximately 29 times higher than that of the parent drug.

MANAGEMENT: Telotristat ethyl should be administered with food.