Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of vanzacaftor, tezacaftor, and deutivacaftor, drugs primarily metabolized by the isoenzyme. Physiologically based pharmacokinetic (PBPK) simulations suggest that coadministration with the potent CYP450 3A4 inducer rifampin may decrease vanzacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) by 78% and 82%, respectively, and may decrease deutivacaftor Cmax and AUC by 80% and 90%, respectively. Similarly, the moderate CYP450 3A4 inducer efavirenz is predicted to decrease vanzacaftor Cmax and AUC by 65% and 69%, respectively; and may decrease deutivacaftor Cmax and AUC by 56% and 73%, respectively. No pharmacokinetic data are available for tezacaftor, but decreased exposures are expected according to prescribing information.

MANAGEMENT: Concomitant use of vanzacaftor, tezacaftor, and deutivacaftor containing medications with potent CYP450 3A4 inducers is not recommended.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of vanzacaftor, tezacaftor, and deutivacaftor, drugs primarily metabolized by the isoenzyme. Physiologically based pharmacokinetic (PBPK) simulations suggest that coadministration with the potent CYP450 3A4 inducer rifampin may decrease vanzacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) by 78% and 82%, respectively, and may decrease deutivacaftor Cmax and AUC by 80% and 90%, respectively. Similarly, the moderate CYP450 3A4 inducer efavirenz is predicted to decrease vanzacaftor Cmax and AUC by 65% and 69%, respectively; and may decrease deutivacaftor Cmax and AUC by 56% and 73%, respectively. No pharmacokinetic data are available for tezacaftor, but decreased exposures are expected according to prescribing information.

MANAGEMENT: Concomitant use of vanzacaftor, tezacaftor, and deutivacaftor containing medications with potent CYP450 3A4 inducers is not recommended.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of vanzacaftor, tezacaftor, and deutivacaftor, drugs primarily metabolized by the isoenzyme. Physiologically based pharmacokinetic (PBPK) simulations suggest that coadministration with the potent CYP450 3A4 inducer rifampin may decrease vanzacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) by 78% and 82%, respectively, and may decrease deutivacaftor Cmax and AUC by 80% and 90%, respectively. Similarly, the moderate CYP450 3A4 inducer efavirenz is predicted to decrease vanzacaftor Cmax and AUC by 65% and 69%, respectively; and may decrease deutivacaftor Cmax and AUC by 56% and 73%, respectively. No pharmacokinetic data are available for tezacaftor, but decreased exposures are expected according to prescribing information.

MANAGEMENT: Concomitant use of vanzacaftor, tezacaftor, and deutivacaftor containing medications with potent CYP450 3A4 inducers is not recommended.

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of tezacaftor, deutivacaftor, and vanzacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In general, the effect of grapefruit juice is concentration-, dose- and preparation- dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. The risk and/or severity of serious side effects such as liver damage may be increased.

ADJUST DOSING INTERVAL: Administration with fat-containing food may increase the oral bioavailability of vanzacaftor and deutivacaftor. Administration with a fat containing meal increased vanzacaftor systemic exposure (AUC) by 4- (low-fat meal) to 6- (high-fat meal) fold. While deutivacaftor AUC increased approximately 3- (low-fat meal) to 4- (high-fat meal) fold, relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with tezacaftor, deutivacaftor, vanzacaftor -containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit. To improve absorption, patients should be advised to take vanzacaftor and/or deutivacaftor containing medications with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products at approximately the same time of the day. A typical cystic fibrosis diet will satisfy this requirement.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of tezacaftor, deutivacaftor, and vanzacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In general, the effect of grapefruit juice is concentration-, dose- and preparation- dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. The risk and/or severity of serious side effects such as liver damage may be increased.

ADJUST DOSING INTERVAL: Administration with fat-containing food may increase the oral bioavailability of vanzacaftor and deutivacaftor. Administration with a fat containing meal increased vanzacaftor systemic exposure (AUC) by 4- (low-fat meal) to 6- (high-fat meal) fold. While deutivacaftor AUC increased approximately 3- (low-fat meal) to 4- (high-fat meal) fold, relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with tezacaftor, deutivacaftor, vanzacaftor -containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit. To improve absorption, patients should be advised to take vanzacaftor and/or deutivacaftor containing medications with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products at approximately the same time of the day. A typical cystic fibrosis diet will satisfy this requirement.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of tezacaftor, deutivacaftor, and vanzacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In general, the effect of grapefruit juice is concentration-, dose- and preparation- dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. The risk and/or severity of serious side effects such as liver damage may be increased.

ADJUST DOSING INTERVAL: Administration with fat-containing food may increase the oral bioavailability of vanzacaftor and deutivacaftor. Administration with a fat containing meal increased vanzacaftor systemic exposure (AUC) by 4- (low-fat meal) to 6- (high-fat meal) fold. While deutivacaftor AUC increased approximately 3- (low-fat meal) to 4- (high-fat meal) fold, relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with tezacaftor, deutivacaftor, vanzacaftor -containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit. To improve absorption, patients should be advised to take vanzacaftor and/or deutivacaftor containing medications with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products at approximately the same time of the day. A typical cystic fibrosis diet will satisfy this requirement.