Drug Interaction Report

MONITOR: Coadministration with ivosidenib may increase plasma concentrations of drugs that are substrates of P-glycoprotein (P-gp) and/or organic anion transporter 3 (OAT3). Based on in vitro studies, ivosidenib may decrease clearance via inhibition of P-gp and OAT3, resulting in increased plasma concentrations of agents that are substrates of these transporters. Clinical and pharmacokinetic data are currently lacking.

MANAGEMENT: Caution is advised if ivosidenib is used concomitantly with substrates of P-gp and/or OAT3. If coadministration is required, clinical and laboratory monitoring may be appropriate whenever ivosidenib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

MONITOR: Coadministration with inducers of CYP450 3A4, particularly those that can also induce uridine diphosphate glucuronosyltransferase (UGT) 1A1, may decrease the plasma concentrations of bictegravir. According to the product labeling, bictegravir is a substrate of both CYP450 3A4 and UGT1A1; however, the extent to which each enzymatic pathway contributes to the metabolic clearance of bictegravir has not been reported. In healthy study subjects, administration of a single 75 mg dose of bictegravir during treatment with rifampin 600 mg once daily decreased mean bictegravir peak plasma concentration (Cmax) and systemic exposure (AUC) by 28% and 75%, respectively, compared to administration of bictegravir alone. When bictegravir 75 mg once daily was coadministered with rifabutin 300 mg once daily, mean bictegravir Cmax, AUC and trough plasma concentration (Cmin) decreased by 20%, 38% and 56%, respectively. These results are consistent with the fact that rifampin is a more potent inducer of CYP450 3A4 than rifabutin. Rifampin is also a known inducer of UGT1A1. The interaction has not been studied with other, less potent inducers than rifampin and rifabutin.

MANAGEMENT: The potential for diminished pharmacologic effects of bictegravir should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivosidenib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. Pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, itraconazole, and the moderate inhibitor, fluconazole. When a single 250 mg dose of ivosidenib was administered with itraconazole 200 mg once daily for 18 days, ivosidenib systemic exposure (AUC) increased to 269% of control, with no change in peak plasma concentration (Cmax). Based on physiologically-based pharmacokinetic modeling, coadministration of a 500 mg dose of ivosidenib with fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control, while multiple-dosing of both is predicted to increase ivosidenib steady-state Cmax and AUC to 152% and 190% of control, respectively. 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. Increased exposure to ivosidenib may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

GENERALLY AVOID: Coadministration with a high-fat meal may increase the plasma concentrations of ivosidenib. According to the product labeling, administration of a single dose with a high-fat meal (approximately 900 to 1000 calories; 500 to 600 calories in fat, 250 calories in carbohydrate, 150 calories in protein) increased ivosidenib Cmax and AUC by 98% and 25%, respectively, in healthy study subjects.

MANAGEMENT: Ivosidenib may be administered with or without food, but should not be administered with a high-fat meal. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with ivosidenib.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.