Levoketoconazole

Uses

Investigated for use/treatment in diabetes mellitus type 2.

How Levoketoconazole works

Preliminary data suggests that DIO-902 increases insulin sensitivity by lowering cortisol levels. The primary mechanism of action is via inhibition of the 11-β-hydroxylase enzyme, the terminal step in cortisol synthesis in the adrenal gland. DIO-902 has also been shown to lower total and LDL-cholesterol by inhibiting 14-α-demethylase, a key enzyme in cholesterol synthesis. In combination with a typical glucose-lowering agent, such as metformin, DIO-902 may enhance glucose control and improve total and LDL-cholesterol. [DiObex Press Release]

Food Interaction

[Moderate] GENERALLY AVOID: Excessive use of alcohol or products containing alcohol together with levoketoconazole may potentiate the risk of liver injury.

Serious hepatotoxicity has been reported with levoketoconazole.

Fatal hepatotoxicity or requiring liver transplantation have 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, excessive use of alcohol or products containing alcohol during 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 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.

However, excessive consumption of alcohol should generally be avoided during levoketoconazole therapy.

Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during levoketoconazole therapy.

Patients receiving 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

Levoketoconazole Disease Interaction

Major: liver impairment/hepatotoxicity, QT prolongationModerate: hypokalemia/hypomagnesemia

Innovators Monograph

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