Clinical Pharmacology Corner: FDA Approves TIBSOVO (Ivosidenib)

FDA Approves TIBSOVO (Ivosidenib) for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with Susceptible IDH1 Mutation

On July 20, 2018, the U.S. Food and Drug Administration (FDA) approved TIBSOVO (ivosidenib) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.  The approved recommended dosage of TIBSOVO is 500 mg orally once daily with or without food for a minimum of 6 months to allow time for clinical response, or until disease progression or unacceptable toxicity. Avoid administration with a high-fat meal. Assess blood counts and blood chemistries prior to TIBSOVO initiation at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Monitor blood creatine phosphokinase weekly for the first month of therapy. Monitor electrocardiograms (ECGs) at least once weekly for the first 3 weeks of therapy, and then at least once monthly for the duration of therapy. See the full prescribing information linked below for recommendations to manage abnormalities or dosage modification guidelines for toxicities.  

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. See the full prescribing information linked below for recommendations to manage abnormalities in QTc.  

Guillain-Barré syndrome can occur in patients treated with TIBSOVO. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) 

• MOA: TIBSOVO inhibits mutant IDH1 enzymes.   
• General PK: Ivosidenib AUC and C_max increase less than proportionally for daily doses of 200 mg to 1,200 mg (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios were approximately 1.9 for AUC and 1.5 for C_max over one month. 
• Absorption: The median time to C_max is approximately 3 hours. Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib C_max by 98% (90% CI: 79%, 119%) and AUC_inf by approximately 25%.
• Distribution: The mean apparent volume of distribution of ivosidenib at steady-state is 234 L (%CV: 47). Protein binding of ivosidenib ranges from 92 to 96% in vitro.
• Elimination: Ivosidenib has a terminal half-life of 93 hours (%CV: 67) and an apparent clearance of 4.3 L/hour (%CV: 50).
• Metabolism: Ivosidenib is primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.
• Excretion: After a single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as unchanged).
• PD: Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies to levels similiar to those observed at baseline in healthy subjects. In bone marrow, 2-HG concentrations were reduced by > 90%.
• Cardiac Electrophysiology: A concentration-dependent QTc interval prolongation of approximately 16.1 msec (90% CI: 13.3, 18.9) was observed at the steady-state C_max. Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline.  

Drug Interactions

• Strong or Moderate CYP3A4 Inhibitors: Consider alternatives therapies that are not strong or moderate CYP3A4 inhibitors during TIBSOVO treatment. If co-administration of a strong CYP3A4 inhibitor is unavoidable, reduce TIBSOVO to 250 mg once daily. Monitor patients for increased risk of QTc interval prolongation.
• Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.  
• Sensitive CYP3A4 or CYP2C9 Substrates: Avoid concomitant use with TIBSOVO, however if unavoidable, monitor patients for loss of therapeutic effect of these substrates. Do not administer TIBSOVO with itraconazole or ketoconazole (CYP3A4 substrates) due to expected loss of anti-fungal efficacy. Patients using hormonal contraceptives should consider alternative methods.
• Drugs that Prolong QTc: Avoid concomitant use with TIBSOVO, however if unavoidable, monitor patients for increased risk of QTc interval prolongation.

Use in Specific Populations

No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38 to 150 kg), ECOG performance status, mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m², MDRD), or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1.0 to 1.5 x ULN and any AST). 

The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m², MDRD), renal impairment requiring dialysis, or moderate or severe hepatic impairment (total bilirubin ≥ 1.5 x ULN and any value for AST) is unknown.

Efficacy and Safety

Efficacy of TIBSOVO was demonstrated at the recommended dosage in an open-label, single-arm, multicenter clinical trial of adult patients with relapsed or refractory AML with an IDH1 mutation, confirmed with the Abbott RealTime IDH1^TM Assay. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

 

The most common adverse reactions (≥ 20%) were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough, and constipation

Full prescribing information is available at https://go.usa.gov/xUUgy. 

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.