Ivosidenib

Uses

Ivosidenib is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia with a susceptible mutation.

Ivosidenib is approved for use in the treatment of relapsed or refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test .

Ivosidenib is also used to associated treatment for these conditions: Refractory, relapsed Acute Myeloid Leukemia

How Ivosidenib works

Ivosidenib is a reversible inhibitor of IDH1 which is non-competitive with respect to the cofactor NADH. It binds to many different 132-substituted IDH1 mutants as well as the wild type enzyme. It is considered to be a slow-binder of the wild type enzyme and binds to mutant enzymes at lower concentrations, both of which may contribute its selectivity . Ivosidenib has not been observed to inhibit any form of IDH2 at micromolar concentrations.

Toxicity

Ivosidenib does not appear to be mutagenic or clastogenic . In rats, uterine atrophy was noted as non-tolerated dose levels in a 90 day repeat dose test with twice daily adiminstration. Carcinogenicity has not been assessed.

Animal embryo-fetal tests suggest Ivosidenib may cause fetal harm in pregnant patients . When administered to pregnant rabbits, embryo-fetal mortality and growth changes occurred starting doses equivalent to 2 times normal recommended human exposure.

Ivosidenib is associated with development of differentiation syndrome presenting as noninfectious leukocytosis , peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and increased serum creatinine. 19% of patients in a clinical trial experienced this.

Ivosidenib is also associated with QTc prolongation . 9% of patients in a clinical trial were found to have a QTc interval greater than 500 msec and 14% had an increase from baseline greater than 60 msec.

Gullain-Barre syndrome is a rare but severe condition associated with Ivosidenib use . <1% of patients in a clinical trial experienced this, presenting as motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing.

Food Interaction

• Do not take with or immediately after a high-fat meal. Administration of ivosidenib with a high-fat meal increases the Cmax and AUC of ivosidenib by 98 and 25%, respectively.
• Exercise caution with grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of ivosidenib. Dose adjustment may be necessary if co-administered.
• Exercise caution with St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of ivosidenib.
• Take at the same time every day.
• Take with or without food.

[Major] 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.

Ivosidenib Drug Interaction

Major: prochlorperazine, ondansetronModerate: donepezilUnknown: multivitamin with minerals, docusate, carvedilol, metformin, furosemide, dronabinol, esomeprazole, cyanocobalamin

Ivosidenib Disease Interaction

Moderate: QTc interval prolongation, renal/hepatic

Volume of Distribution

Ivosidenib has a mean apparent Vd of 234 L at steady-state .

Elimination Route

Ivosidenib has a Tmax of 3 hours following oral administration of a 2 250 mg tablets (total 500 mg) . When given with a high-fat meal, Cmax increases by 98% and AUC by 25%.

The AUC and Cmax increase in a less than dose-proportional manner in the range of 200-1200 mg daily . Accumulation ratios have been determined to be 1.9 for AUC and 1.5 for Cmax over the course of one month. Steady state is known to be reached within 14 days of daily administration.

Half Life

Ivosidenib has a terminal half-life of 93 h .

Clearance

Ivosidenib has an apparent clearance rate of 4.3 L/h

Elimination Route

Following oral administration, 77% of Ivosidenib is eliminated in the feces with 67% present as the parent drug . 17% is excreted in the urine with 10% as the parent drug.

No clinically meaningful effects on elimination have been observed with mild to moderate renal impairment or mild hepatic impairment . Changes in patients with severe renal impairment or moderate too severe hepatic impairment have not been investigated.

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