Population pharmacokinetic and exposure‐response analyses of ivosidenib in patients with <i>IDH1</i>‐mutant advanced hematologic malignancies

Jiang, Xiaorui; Wada, Russ; Poland, Bill; Kleijn, Huub Jan; Fan, Bin; Li, Xinwei; Liu, Hua; Kapsalis, Stephanie K.; Yang, Hua; Le, Kha

doi:10.1111/cts.12959

Cited by 8 publications

(6 citation statements)

References 20 publications

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“…Ivosidenib is rapidly absorbed (median time to maximum concentration [ T max ] was typically 2–4 h) and concentrations slowly declined with a mean terminal half‐life ( t ½ ) of ~72–138 h after single dosing and multiple doses in patients with hematologic malignancies. Ivosidenib exhibited an increase in apparent clearance after multiple dose administration which was attributed to a decrease in bioavailability due to auto‐induction of CYP3A4 50 . Ivosidenib is a substrate and an inducer of CYP3A4 and also induces CYP2B6, and CYP2C enzymes.…”

Section: Strong Cyp3a Inducersmentioning

confidence: 99%

“…Ivosidenib exhibited an increase in apparent clearance after multiple dose administration which was attributed to a decrease in bioavailability due to auto‐induction of CYP3A4. 50 Ivosidenib is a substrate and an inducer of CYP3A4 and also induces CYP2B6, and CYP2C enzymes. PBPK modeling was used to predict magnitude of CYP2B6, CYP2C8, CYP2C9, and CYP3A4 induction of ivosidenib along with other DDI predictions in patients with cancer.…”

Section: Strong Cyp3a Inducersmentioning

confidence: 99%

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Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Bolleddula

Gopalakrishnan

et al. 2022

Clinical Translational Sci

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N‐Nitrosamine (NA) impurities are considered genotoxic and have gained attention due to the recall of several marketed drug products associated with higher‐than‐permitted limits of these impurities. Rifampicin is an index inducer of multiple cytochrome P450s (CYPs) including CYP2B6, 2C8, 2C9, 2C19, and 3A4/5 and an inhibitor of OATP1B transporters (single dose). Hence, rifampicin is used extensively in clinical studies to assess drug–drug interactions (DDIs). Despite NA impurities being reported in rifampicin and rifapentine above the acceptable limits, these critical anti‐infective drugs are available for therapeutic use considering their benefit–risk profile. Reports of NA impurities in rifampicin products have created uncertainty around using rifampicin in clinical DDI studies, especially in healthy volunteers. Hence, a systematic investigation through a literature search was performed to determine possible alternative index inducer(s) to rifampicin. The available strong CYP3A inducers were selected from the University of Washington DDI Database and their in vivo DDI potential assessed using the data from clinical DDI studies with sensitive CYP3A substrates. To propose potential alternative CYP3A inducers, factors including lack of genotoxic potential, adequate safety, feasibility of multiple dose administration to healthy volunteers, and robust in vivo evidence of induction of CYP3A were considered. Based on the qualifying criteria, carbamazepine, phenytoin, and lumacaftor were identified to be the most promising alternatives to rifampicin for conducting CYP3A induction DDI studies. Strengths and limitations of the proposed alternative CYP3A inducers, the magnitude of in vivo CYP3A induction, appropriate study designs for each alternative inducer, and future perspectives are presented in this paper.

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Section: Strong Cyp3a Inducersmentioning

confidence: 99%

Section: Strong Cyp3a Inducersmentioning

confidence: 99%

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Bolleddula

Gopalakrishnan

et al. 2022

Clinical Translational Sci

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“…However, the clinical trials included in our study did not specify dose reductions to account for this interaction, nor is a dose reduction routinely done in our clinical practice. Although we were unable to determine whether a dose reduction of ivosidenib may have resulted in a reduced interaction with triazole antifungals, physiologically based pharmacokinetic studies have shown that ivosidenib exhibits CYP3A4 autoinduction effects at all dose levels of ivosidenib 5,28 . Routine utilization of triazole antifungals and ivosidenib 500 mg daily may not result in an increased rate of observed QTc prolongation partially because of the fact that the serum levels of the azole antifungals are being diminished by ivosidenib itself.…”

Section: Discussionmentioning

confidence: 92%

Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome

Dinh,

Savoy,

Kontoyiannis

et al. 2024

Cancer

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BackgroundIvosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P‐glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P‐glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown.MethodsPatients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole.ResultsSeventy‐eight serum triazole levels from 31 patients receiving ivosidenib‐containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily.ConclusionsThis study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high‐dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.

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Section: Isocitrate Dehydrogenase Inhibitorsmentioning

confidence: 99%

“…31 However, a population pharmacokinetic analysis observed that increasing area under the curve (AUC) in the presence of azoles was not associated with an increase in clinical toxicity, likely indicating a wide therapeutic window. 32 As a result, the current expert opinion is to exercise "caution" in the presence of azoles and monitor the QTc interval closely while continuing the drug at the full dose of 500 mg per day. 33 No significant safety concerns were highlighted on using a combination of ivosidenib with azacytidine and venetoclax in a phase Ib/III study, indicating a potentially new combination for IDH1-mutated AML.…”

Section: Ivosidenibmentioning

confidence: 99%

FLT3 and IDH1/2 Inhibitors for Acute Myeloid Leukemia: Focused Clinical Narrative Review of Forthcoming Drugs from an Indian Context

Singh,

Jain,

Singh

et al. 2024

Indian J Med Paediatr Oncol

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Therapeutic approaches for acute myeloid leukemia (AML) have witnessed minimal evolution in recent decades, primarily relying on advancements in supportive care and transplantation to drive improvements in overall survival rates. However, treatment with intensive chemotherapy may not be feasible for patients with advanced age or reduced fitness, and outcomes for patients with relapsed/refractory disease continue to be suboptimal. Several agents with a novel mechanism of action have been developed in the past decade and have shown efficacy in patients with both newly diagnosed and relapsed AML. Out of these, several FLT3 (FMS like tyrosine kinase 3) and IDH1/2 (isocitrate dehydrogenase 1/2) inhibitors have received regulatory approval in specific clinical settings and are available for clinical use. This is an actively expanding field with several ongoing clinical trials in advanced phases. We provide a focused narrative review of drugs from these two categories with available clinical data.

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Population pharmacokinetic and exposure‐response analyses of ivosidenib in patients with IDH1‐mutant advanced hematologic malignancies

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 8 publications

References 20 publications

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome

FLT3 and IDH1/2 Inhibitors for Acute Myeloid Leukemia: Focused Clinical Narrative Review of Forthcoming Drugs from an Indian Context

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