Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of P-glycoprotein (P-gp) or CYP450 3A4 may significantly decrease the plasma concentrations of glecaprevir and pibrentasvir. Both antiviral agents are substrates of the P-gp efflux transporter, and glecaprevir is additionally a substrate of the CYP450 3A4 isoenzyme. When a single 300 mg-120 mg dose of glecaprevir-pibrentasvir was administered to 12 study subjects following multiple dosing of the potent inducer rifampin at 600 mg once daily, glecaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 86% and 88%, respectively, while pibrentasvir Cmax and AUC decreased by 83% and 87%, respectively. Likewise, when a single dose of glecaprevir-pibrentasvir was administered to 10 study subjects following multiple dosing of carbamazepine 200 mg twice daily, glecaprevir Cmax and AUC decreased by approximately two-thirds, while pibrentasvir Cmax and AUC decreased by approximately one-half.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of glecaprevir and pibrentasvir with potent P-gp or CYP450 3A4 inducers is not recommended.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of glecaprevir and pibrentasvir. Relative to fasting conditions, mean glecaprevir systemic exposure (AUC) increased by 83% to 163% and mean pibrentasvir AUC increased by 40% to 53% when administered with moderate to high fat meals.

MANAGEMENT: Glecaprevir-pibrentasvir should be administered with food.