Interactions between Levoketoconazole and Vorasidenib

Generally avoid

The concomitant administration of strong CYP450 3A4 inducers may significantly reduce levoketoconazole serum levels. There are no data about the interaction between strong CYP450 3A4 inducers and levoketoconazole. However, there are data for ketoconazole, of which levoketoconazole is an enantiomer. When ketoconazole 400 mg/day was coadministered with the strong CYP450 3A4 inducer nevirapine 200 mg/day for 14 days, followed by 400 mg/day for 14 days, the area under the concentration-time curve (AUC) of ketoconazole decreased by an average of 72% and the maximum plasma concentration (Cmax) decreased by 44%. Nevirapine plasma AUCs increased by 15% to 28%, which is not considered clinically significant. The mechanism appears to be enhanced first-pass metabolism and hepatic enzyme metabolism (CYP450 3A4) of the azole agent.

Management

Levoketoconazole manufacturer recommends avoiding concomitant therapy with potent CYP450 3A4 inducers from 2 weeks before and during treatment with levoketoconazole.

Generally avoid

Excessive use of alcohol or products containing alcohol together with ketoconazole or levoketoconazole may potentiate the risk of liver injury. Serious hepatotoxicity has been reported with levoketoconazole. Hepatotoxicity requiring liver transplantation has been reported with the use of oral ketoconazole, of which levoketoconazole is an enantiomer. Some patients had no obvious risk factors for liver disease. In addition, use of alcohol or products containing alcohol during ketoconazole or levoketoconazole therapy may result in a disulfiram-like reaction in some patients. Symptoms of disulfiram-like reaction include flushing, rash, peripheral edema, nausea, and headache.

Generally avoid

Coadministration with grapefruit juice may increase the plasma concentrations of ketoconazole or levoketoconazole. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. When administered to healthy volunteers with a high-fat meal (875 calories; 62% fat), levoketoconazole systemic exposure (AUC) increased by 30% while peak plasma concentration (Cmax) did not change and the time to reach Cmax (Tmax) was delayed from 2 to 4 hours, compared to fasted conditions.

Management

Levoketoconazole may be administered with or without food. Excessive consumption of alcohol should generally be avoided during ketoconazole or levoketoconazole therapy. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during ketoconazole or levoketoconazole therapy. Patients receiving ketoconazole or levoketoconazole should be instructed to contact their doctor immediately if they experience swelling, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage.

Generally avoid

Smoking tobacco during treatment may decrease vorasidenib plasma concentrations and reduce its anti-tumor activity. The mechanism is tobacco smoking-mediated induction of CYP450 1A2, the isoenzyme primarily responsible for the metabolic clearance of vorasidenib. Clinical and pharmacokinetic data are currently lacking. In addition, because vorasidenib can cause hepatotoxicity, concomitant use with alcohol may further increase the risk of liver injury. Clinical data evaluating this interaction are also lacking.

Monitor

In pharmacokinetic studies, food increased vorasidenib exposure. High-fat meals increased vorasidenib systemic exposure (AUC) and peak plasma concentration (Cmax) by 1.4-fold and 3.1-fold, respectively, while low-fat meals increased AUC and Cmax by 1.4-fold and 2.3-fold, respectively. However, the manufacturer does not consider this effect as clinically significant.

Management

Patients should be advised to avoid smoking tobacco during treatment with vorasidenib. According to its product labeling, vorasidenib may be taken with or without food. In addition, patients should be advised to avoid excessive alcohol consumption during treatment. Liver function tests should be monitored according to the manufacturer's recommendations, and patients should promptly report signs and symptoms of liver injury.