Preclinical Drug Metabolism, Pharmacokinetic, and Pharmacodynamic Profiles of Ivosidenib, an Inhibitor of Mutant Isocitrate Dehydrogenase 1 for Treatment of Isocitrate Dehydrogenase 1-Mutant Malignancies

Nagaraja, N.; Fan, Bin; Utley, Luke; Lemieux, René M.; Popovici‐Muller, Janeta; Dang, Lenny; Kim, Hyeryun; Yan, Liping; Su, Shinsan M.; Biller, Scott A.; Yang, Hua

doi:10.1124/dmd.120.000234

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…Although IDH enzymes normally catalyse the oxidation of isocitrate to 2-oxoglutarate by NAD(P) + , certain mutations associated with cancers result in a gain-of-function activity—catalysis of the reduction of 2-oxoglutarate to 2-hydroxyglutarate by NAD(P)H 69 , 70 . The IDH1 R132H variant is inhibited by a drug known as Ivosidenib 71 , which is in clinical use.…”

Section: Advantages and Applicationsmentioning

confidence: 99%

Interactive biocatalysis achieved by driving enzyme cascades inside a porous conducting material

Siritanaratkul,

Megarity,

Herold

et al. 2024

Commun Chem

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An emerging concept and platform, the electrochemical Leaf (e-Leaf), offers a radical change in the way tandem (multi-step) catalysis by enzyme cascades is studied and exploited. The various enzymes are loaded into an electronically conducting porous material composed of metallic oxide nanoparticles, where they achieve high concentration and crowding – in the latter respect the environment resembles that found in living cells. By exploiting efficient electron tunneling between the nanoparticles and one of the enzymes, the e-Leaf enables the user to interact directly with complex networks, rendering simultaneous the abilities to energise, control and observe catalysis. Because dispersion of intermediates is physically suppressed, the output of the cascade – the rate of flow of chemical steps and information – is delivered in real time as electrical current. Myriad enzymes of all major classes now become effectively electroactive in a technology that offers scalability between micro-(analytical, multiplex) and macro-(synthesis) levels. This Perspective describes how the e-Leaf was discovered, the steps in its development so far, and the outlook for future research and applications.

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Section: Advantages and Applicationsmentioning

confidence: 99%

Interactive biocatalysis achieved by driving enzyme cascades inside a porous conducting material

Siritanaratkul,

Megarity,

Herold

et al. 2024

Commun Chem

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“…Ivosidenib has been extensively studied before being used in clinical trials to determine the best route of administration, its effects on the P450 enzyme complex, and ways to improve efficacy. A single 10 mg/kg dose of ivosidenib orally showed good absorption and bioavailability of 48% in preclinical studies and was hence used as a convenient oral drug, improving patient compliance [ 18 ]. Although it did have good bioavailability, it has poor central nervous system (CNS) penetration and hence might probably be ineffective if given orally to CNS tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Ivosidenib is associated with weak direct inhibition of CYP2C8, CYP2C19, CYP2D6, and CYP3A4/6. It also causes an increase in CYP2B6 activity [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Isocitrate Dehydrogenase 1 Mutation and Ivosidenib in Patients With Acute Myeloid Leukemia: A Comprehensive Review

Tangella,

Gajre,

Kantheti

2023

Cureus

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Acute myeloid leukemia (AML) arises from immature myeloid progenitors, resulting in a stem-cell-like proliferative state. This leads to excessive pools of immature cells that cannot function, which usually happens at the cost of the production of mature functional cells, leading to deleterious consequences. The management of AML has intensified as newer targeted therapies have come into existence owing to deeper genetic analysis of the disease and patients. Isocitrate dehydrogenase (IDH) is a cytosolic enzyme that is a part of the Krebs cycle and is extremely important in maintaining the homeostasis of the cell. It is produced by two different genes: IDH1 and IDH2. Ivosidenib has been associated with IDH1 inhibition and has been studied in numerous cancers. This review highlights the studies that have dealt with ivosidenib, an IDH1 inhibitor, in AML, the side effect profile, and the possible future course of the drug. After a scoping review of the available literature, we have identified that studies have consistently shown positive outcomes and that ivosidenib is a promising avenue for the management of AML. But it also has to be kept in mind that resistance to IDH inhibitors is on the rise, and the need to identify ways to circumvent this is to be addressed.

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A Simple HPLC-UV Method for Ivosidenib Determination in Human Plasma

Gando,

Yasu

2023

Journal of Chromatographic Science

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Ivosidenib is used for the treatment of acute myeloid leukemia (AML) with isocitrate dehydrogenase 1 (IDH1) mutations. However, increased blood concentrations of ivosidenib are associated with a risk of a prolonged QT interval in patients with AML. Therapeutic drug monitoring in patients with AML with IDH1 mutation offers the potential to improve treatment efficacy while minimizing toxicity. In this study, we developed an efficient high-performance liquid chromatography–ultraviolet (HPLC-UV) method for the quantification of ivosidenib in plasma. Human plasma samples (50 μL) were processed by protein precipitation using acetonitrile, followed by chromatographic separation on a reversed-phase column with an isocratic mobile phase of 0.5% KH₂PO₄ (pH 4.5) and acetonitrile (45:55, v/v) at a flow rate of 1.0 mL/min, with ultraviolet detection at 245 nm. Calibration curves were linear over the range of 0.25–20 μg/mL with a coefficient of determination (r2) of 0.99999. Intra-day and inter-day precision were 1.20–8.04% and 0.69–4.20%, respectively. The assay accuracy was −2.00% to 1.93% and recovery was >91.2%. These findings support the effectiveness of the newly developed HPLC-UV method for the quantification of ivosidenib in human plasma. This simple and cost-effective method is expected to expand ivosidenib monitoring in laboratories lacking LC–MS/MS instruments.

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Preclinical Drug Metabolism, Pharmacokinetic, and Pharmacodynamic Profiles of Ivosidenib, an Inhibitor of Mutant Isocitrate Dehydrogenase 1 for Treatment of Isocitrate Dehydrogenase 1-Mutant Malignancies

Cited by 5 publications

References 24 publications

Interactive biocatalysis achieved by driving enzyme cascades inside a porous conducting material

Interactive biocatalysis achieved by driving enzyme cascades inside a porous conducting material

Isocitrate Dehydrogenase 1 Mutation and Ivosidenib in Patients With Acute Myeloid Leukemia: A Comprehensive Review

A Simple HPLC-UV Method for Ivosidenib Determination in Human Plasma

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