Ivosidenib

Introduction Overview

Generic Name

ivosidenib

Brand Name

Tibsovo

Dosage Form

oral tablets

Drug Class

Miscellaneous antineoplastics

Pharmacokinetics

Absorption: Ivosidenib is administered orally in tablet form and is absorbed through the gastrointestinal tract. It has demonstrated adequate bioavailability when taken with or without food. Clinical pharmacokinetic studies indicate that the maximum plasma concentration (Cmax) is typically reached within a few hours post-administration, demonstrating rapid uptake. The absorption phase is consistent and predictable, although high-fat meals may alter its pharmacokinetic profile by increasing plasma concentrations; thus, concomitant intake with high-fat foods is advised against to avoid altered drug exposure. Distribution: Following absorption, ivosidenib exhibits extensive distribution throughout body tissues, relevant to its targeting of malignant cells including those found in bone marrow and biliary tract tissues. It is moderately bound to plasma proteins, primarily albumin, which affects its free active drug concentration and distribution volume. Ivosidenib's ability to penetrate target tissues and its binding to intracellular isocitrate dehydrogenase-1 enzymes underscore its therapeutic efficacy. Metabolism: Ivosidenib undergoes hepatic metabolism predominantly through CYP3A4 enzymes, leading to multiple metabolites, none of which have clinically meaningful anti-cancer activity. The metabolism is influenced by concomitant administration of CYP3A4 inhibitors or inducers, thus caution is advised when prescribing alongside such agents. This metabolic pathway highlights the potential for drug interactions and necessitates monitoring or dose adjustments accordingly. Elimination: The drug and its metabolites are eliminated primarily via fecal excretion, with a lesser extent eliminated renally. The terminal half-life averages approximately 93 hours, supporting once-daily dosing regimens. Elimination kinetics are influenced by liver function, with caution warranted in hepatic impairment. Clinical trials have demonstrated steady-state plasma concentrations reached around 14 days, ensuring therapeutic consistency with routine dosing.

Dosage Forms

Available Dosage Forms: Tibsovo is supplied as oral tablets containing ivosidenib 250 mg as the active ingredient. Each tablet also contains inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, and tablet coating components such as FD&C blue #2, hypromellose, lactose monohydrate, titanium dioxide, and triacetin. Dosages for Adults and Adolescents: The recommended dosage for adult patients is 500 mg (administered as two 250 mg tablets) once daily, with or without food. Treatment adherence to once-daily dosing is critical to maintaining therapeutic plasma levels. Specific Patient Populations: There is limited information regarding the safe and effective use of Tibsovo in pediatric patients, and it is not approved for use in children. In patients with hepatic or renal impairment, dosing adjustments may be considered carefully based on clinical judgment and monitoring of adverse effects. Patients are advised to avoid high-fat meals concurrently with the medication to prevent modifications in drug absorption and plasma levels. Clinical guidelines recommend dosage adjustment or enhanced monitoring in patients who are concomitantly taking strong CYP3A4 inhibitors or inducers due to the substantial effect on ivosidenib metabolism.

Mechanism Of Action

Ivosidenib (Tibsovo) functions as a targeted inhibitor of the isocitrate dehydrogenase-1 (IDH1) enzyme, which is mutated in certain malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes, and cholangiocarcinoma. Normally, wild-type IDH1 catalyzes the conversion of isocitrate to alpha-ketoglutarate in the cytoplasm, generating NADPH crucial for cellular metabolism and regulation of oxidative stress. However, mutated IDH1 results in a gain-of-function enzymatic activity that abnormally converts alpha-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG). Elevated 2-HG levels disrupt normal cellular differentiation and epigenetic regulation, contributing to oncogenesis. Ivosidenib selectively binds to the mutant IDH1 enzyme, inhibiting its aberrant activity and subsequently decreasing intracellular 2-HG concentrations. This reduction alleviates the blockage of cellular differentiation, allowing immature myeloid cells to mature properly and reducing the leukemic blast population. Cellular effects include decreased proliferation of malignant progenitor cells and restoration of normal hematopoiesis. Clinical studies demonstrate that lowering 2-HG levels correlates with improved remission rates and clinical outcomes in patients harboring IDH1 mutations. Compared to other treatments, ivosidenib offers a precision medicine approach by targeting a specific molecular alteration rather than broadly cytotoxic chemotherapies. Research evidences from phase I/II clinical trials confirm its efficacy in relapsed/refractory AML and in combination therapy for newly diagnosed AML in patients ineligible for intensive chemotherapy. The mechanism establishes a paradigm shift in treating IDH1-mutated cancers by rectifying metabolic dysregulation driving malignancy.

Pharmacological Actions

Selective inhibition of mutant isocitrate dehydrogenase-1 (mIDH1) enzyme activity.
Reduction of oncometabolite D-2-hydroxyglutarate levels in malignant cells.
Restoration of normal cellular differentiation pathways in hematopoietic cells.
Decreased proliferation of leukemic blasts in bone marrow.
Modulation of epigenetic and metabolic derangements caused by IDH1 mutation.
Exertion of antineoplastic activity in acute myeloid leukemia and cholangiocarcinoma.
Synergistic efficacy when combined with hypomethylating agents such as azacitidine.
Potential to overcome resistance to conventional chemotherapy targeting mutant clones.
Minimal impact on wild-type IDH1 enzyme function, preserving normal cellular metabolism.
Improvement of hematologic parameters by reducing immature malignant cells.
Targeted therapy approach reducing off-target cytotoxicity.
Long half-life supporting sustained once-daily dosing and consistent plasma drug levels.
Capacity to cross cellular membranes to reach cytosolic mutant enzymes.
Non-cytotoxic mechanism leading to favorable tolerability profile in patients.
Potential inhibition of downstream pro-oncogenic signaling pathways resulting from mutant enzyme activity.

Therapeutic Or Clinical Uses

Treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring a susceptible IDH1 mutation.
First-line therapy for newly diagnosed AML patients with a confirmed IDH1 mutation who are 75 years or older or who have comorbidities precluding intensive induction chemotherapy, given as monotherapy.
Combination therapy with azacitidine for newly diagnosed AML with IDH1 mutation in patients unsuitable for standard chemotherapy.
Treatment of adult patients with relapsed or refractory myelodysplastic syndromes with susceptible IDH1 mutation.
Management of advanced or metastatic cholangiocarcinoma (bile duct cancer) harboring the IDH1 mutation after progression on prior systemic therapies.
Targeted molecular therapy for malignancies characterized by IDH1 mutation-associated metabolic derangement.
Therapeutic option where conventional chemotherapy is contraindicated or ineffective due to patient factors or molecular resistance.
Use as part of precision oncology treatment paradigms based on genetic mutation profiling.
Adjunct therapy aimed at improving hematologic response rates and survival outcomes in AML patients with IDH1 mutation.
Option for patients with limited treatment alternatives owing to advanced disease states.
Potential use in clinical trials exploring expanded malignancy types with IDH1 mutation.
Addresses unmet medical need in difficult-to-treat hematologic and biliary cancers.
Treatment to reduce blast counts and enhance mature myeloid cell recovery in bone marrow disorders.
FDA-approved indication since 2018 for targeted inhibition of mutated IDH1 enzyme activity.
Use guided by FDA-approved companion diagnostic tests confirming the presence of IDH1 mutation.

Side Or Adverse Effects

Differentiation syndrome presenting with fever, respiratory distress, hypotension, rash, edema, rapid weight gain, and decreased urine output, potentially fatal if untreated.
QTc interval prolongation leading to risk of serious, life-threatening cardiac arrhythmias including torsades de pointes.
Guillain-Barré syndrome manifesting as progressive muscle weakness, sensory disturbances, and respiratory compromise.
Common adverse effects such as nausea, vomiting, and diarrhea affecting gastrointestinal tolerance.
Stomach pain or abdominal swelling reported frequently among patients.
Anorexia leading to weight loss and potential nutritional compromise.
Fatigue and general tiredness impacting quality of life and functional status.
Respiratory symptoms including cough and shortness of breath during treatment.
Oral mucositis presenting as sores or ulcers in the mouth or throat.
Rash and dermatologic reactions varying in severity.
Elevated liver enzyme levels indicating hepatic toxicity or liver function abnormalities.
Musculoskeletal complaints including muscle and joint pains.
Peripheral edema notably in the arms or legs.
Electrolyte disturbances requiring monitoring, particularly of potassium, sodium, and magnesium.
Potential allergic reactions including urticaria, swelling, and respiratory distress necessitating emergency care.

Precautions

Perform baseline and periodic electrocardiograms (ECG) to monitor QTc interval before and during therapy.
Monitor for signs and symptoms of differentiation syndrome promptly to initiate corticosteroid treatment if needed.
Assess for neurological symptoms indicative of Guillain-Barré syndrome, and discontinue drug if confirmed.
Evaluate hepatic and renal function prior to and during treatment to identify toxicity or need for dose adjustment.
Avoid coadministration with strong or moderate CYP3A4 inhibitors and inducers due to altered plasma drug concentrations and risk of toxicity or therapeutic failure.
Advise patients to avoid high-fat meals concurrently with dosing to prevent changes in drug absorption and efficacy.
Screen women of childbearing potential for pregnancy and advise effective contraception during and for at least one month post-treatment due to fetal risk.
Caution in patients with history of cardiac disease, long QT syndrome (personal or familial), or electrolyte imbalances requiring correction prior to initiating therapy.
Advise against breastfeeding during treatment and for one month after the last dose due to unknown excretion in breast milk.
Maintain hydration to support renal function and mitigate gastrointestinal side effects.
Continuous monitoring of blood counts to detect cytopenias or hematologic toxicity.
Educate patients on recognizing early adverse effects to ensure timely medical intervention.
Close follow-up for patients with pre-existing liver cirrhosis or dialysis due to altered drug handling and safety profile.
Document and manage any hypersensitivity reactions appropriately.
Regular assessment of concomitant medications to avoid potential harmful drug interactions.

Warnings

Risk of QTc interval prolongation which can lead to life-threatening arrhythmias such as torsades de pointes.
Potential development of differentiation syndrome which may be fatal if not recognized and treated promptly.
Occurrence of Guillain-Barré syndrome in a small percentage of patients necessitating immediate discontinuation and treatment.
Not established safety and efficacy in pediatric populations; use limited to adults.
Possibility of serious allergic reactions including anaphylaxis requiring emergency medical care.
Increased risk of toxicity when combined with other QTc prolonging agents necessitating ECG monitoring.
Potential harm to fetus; pregnancy must be avoided during therapy and monitored carefully.
Risk of diminished efficacy of hormonal contraceptives due to interaction with ivosidenib, requiring alternative contraceptive methods.
Patients with electrolyte imbalances or cardiac disease are at increased risk of adverse cardiac events.
Caution in patients with hepatic or renal impairment due to altered drug metabolism and elimination.
Risk of treatment interruption or discontinuation due to serious adverse events impacting clinical outcomes.
Necessity of monitoring laboratory parameters including liver enzymes and blood counts to detect early toxicity.
Avoidance of high-fat meals around dosing to minimize absorption variability.
Potential interactions with a wide range of medications including antimicrobials, psychotropics, and antivirals.
Adherence to prescribed dosing schedule is essential to prevent suboptimal drug exposure and resistance development.

Contraindication

Known hypersensitivity or allergy to ivosidenib or any component of the formulation.
Concurrent use with strong or moderate CYP3A4 inducers due to risk of significantly reduced therapeutic efficacy.
History of long QT syndrome or congenital prolonged QT interval without appropriate monitoring and risk mitigation.
Patients with uncontrolled cardiac arrhythmias or unstable cardiovascular conditions.
Pregnancy due to potential fetal harm and lack of safety data.
Breastfeeding mothers where drug passage into milk may pose risks to the infant.
Co-administration with other drugs that significantly prolong QT interval without capacity for close monitoring.
Severe hepatic impairment without established dosing guidance and risk of accumulation.
Children and adolescents due to unestablished safety and efficacy profiles.
Patients unable to adhere to required monitoring protocols or dosing instructions.
Concomitant use with medications known to cause serious overlapping toxicities without dose adjustment.
Known hypersensitivity to dyes or excipients within the tablet coating that could cause allergic reaction.
Drug interactions with other antineoplastics requiring contraindication if combined without evidence-based rationale.
Active infection or comorbid conditions precluding safe administration of oral antineoplastic therapy.
Presence of electrolyte abnormalities that cannot be corrected prior to therapy initiation.

Drug Interactions

Strong or moderate CYP3A4 inhibitors such as clarithromycin, ketoconazole, itraconazole, nefazodone, ritonavir, and atazanavir which can increase ivosidenib plasma concentrations, increasing toxicity risk.
Strong or moderate CYP3A4 inducers including rifampicin, phenobarbital, phenytoin, St. John's Wort, and glucocorticoids that reduce ivosidenib efficacy by decreasing plasma concentrations; coadministration is contraindicated.
Sensitive CYP3A4 substrates like hormonal contraceptives and lenacapavir that may have altered efficacy or increased toxicity when co-administered with ivosidenib.
Concurrent use with QTc-prolonging agents (e.g., amiodarone, haloperidol, quetiapine, flecainide) heightens the risk of cardiac arrhythmias and necessitates ECG monitoring and caution.
Drugs with overlapping toxicities such as hepatotoxic agents leading to additive liver function abnormalities.
Potential interaction with other antineoplastic agents may augment hematologic toxicity requiring close monitoring.
Medications affecting electrolyte balance may increase risk of QTc prolongation during ivosidenib therapy.
Agents that alter gastric pH or motility could potentially affect absorption, though no direct data confirm this.
Herbal supplements and vitamins that modulate CYP3A4 enzymes could unpredictably affect drug metabolism.
Interaction with anticoagulants or antiplatelet agents warrants assessment of bleeding risk given the underlying hematologic malignancy.
Concomitant administration of drugs metabolized by CYP3A4 may experience altered plasma levels due to inhibition or induction by ivosidenib.
Avoidance of grapefruit or grapefruit juice, which can inhibit CYP3A4 and increase systemic exposure.
Potential interactions with antiviral medications used in HIV or hepatitis treatments requiring dose adjustments.
Monitoring strategies recommended when initiating or discontinuing interacting medications to adjust Tibsovo dosing accordingly.
Comprehensive medication review essential prior to initiation to anticipate and mitigate drug-drug interactions.

Preparations Of The Drug

Tibsovo oral tablets containing 250 mg of active ingredient ivosidenib per tablet.
Tablet formulation designed for once-daily oral administration.
Film-coated tablets including inactive excipients such as colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, and coloring agents.
Packaging includes a desiccant canister within the bottle to maintain stability under specified storage conditions.
Storage recommendations specify room temperature between 68°F to 77°F (20°C to 25°C), avoiding moisture and excessive heat.
Shelf-stable formulation with recommended storage away from children and in original container to preserve integrity.
Available only by prescription and requiring appropriate patient counseling on administration and adherence.
Manufactured by Servier Pharmaceuticals LLC with quality controls ensuring consistent drug concentration per tablet.
No available liquid or injectable formulations; exclusively oral tablet dosage form.
Guidelines recommend swallowing tablets whole without crushing, chewing, or breaking to maintain drug release characteristics.
Contains coloring agents FD&C blue #2 and other excipients, of note in patients with sensitivities.
Tablets supplied in standard counts appropriate for one-month treatment supply.
Prescribed and dispensed with accompanying medication guides outlining adverse effect management and interactions.
Available in formulations specifically dosed for adult therapy, with no pediatric formulations currently marketed.
Patient education materials accompany the medication to emphasize storage, dosing instructions, and precautions.