Drug Interactions between nintedanib and telotristat

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of nintedanib. After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions. Absorption was also delayed, as indicated by an increase in the median time to reach maximum plasma concentration (Tmax) from 2 hours in the fasted state to approximately 4 hours under fed conditions, irrespective of the type of food ingested. In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolate pudding for up to 15 minutes did not have any impact on their pharmaceutical quality, but swelling and deformation of the capsules were observed with longer exposure time due to water uptake of the gelatin capsule shell. Therefore, administration with soft food would not be expected to alter the clinical effect of nintedanib when taken immediately.

GENERALLY AVOID: Grapefruit and grapefruit juice may increase the plasma concentrations of nintedanib, which has been shown to be a substrate of the P-glycoprotein (P-gp) efflux transporter and a minor substrate of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of both P-gp-mediated efflux in the gut wall as well as CYP450 3A4-mediated first-pass metabolism in the intestinal tract by certain compounds present in grapefruit.

MANAGEMENT: Nintedanib should be administered with food to reduce the incidence of gastrointestinal effects. Nintedanib capsules may be taken with water or a small amount (teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding, and must be swallowed whole (unchewed) immediately, to ensure the capsule stays intact. Food containing grapefruit, grapefruit juice, Seville orange (a citrus relative of the grapefruit), or Seville orange juice should be avoided during treatment with nintedanib.

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.