Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment

Gupta, Neeraj; Hanley, Michael; Venkatakrishnan, Karthik; Perez, Raymond P.; Norris, Robin E.; Nemunaitis, John; Yang, Huyuan; Qian, Mark G.; Labotka, Richard; Fu, Siqing

doi:10.1111/bcp.12991

Cited by 40 publications

(56 citation statements)

References 22 publications

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“…Blood samples were collected for ixazomib PK analysis at multiple points pre-and postdosing during cycle 1: before dosing (within 1 hour) on days 1 and 15 of cycle 1, and day 1 of cycle 2, as well as at 30 minutes and 1, 2, 4, 6, 24, and 168 hours after ixazomib administration on days 1 and 15 of cycle 1. Plasma and whole-blood concentrations of ixazomib were measured using a validated liquid chromatography/tandem mass spectrometry assay 35 after dosing on days 1 and 15. Hematologic response assessment was based on the difference between involved and uninvolved free light chain according to standardized criteria 17 ; the baseline was set at screening, and levels were evaluated during the rest period of each cycle, at the end-of-treatment visit, and every 6 weeks thereafter by central laboratory.…”

Section: Assessmentsmentioning

confidence: 99%

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

Sanchorawala

Palladini

Kukreti

et al. 2017

Blood

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116

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This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902. A phase 3 study is ongoing (#NCT01659658).

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Section: Assessmentsmentioning

confidence: 99%

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

Sanchorawala

Palladini

Kukreti

et al. 2017

Blood

Self Cite

116

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“…In this type of pml, prompt plasmapharesis is recommended as it accelerates drug clearance 2,22 . As ixazomib is a highly protein-bound drug, plasmapharesis might also accelerate its clearance and possibly improve outcomes; however, this remains unproven 23,24 . Regardless of treatment approach, a heightened vigilance for-and early detection of-pml is key to achieving better outcomes.…”

Section: Figurementioning

confidence: 99%

Progressive Multifocal Leukoencephalopathy during Ixazomib-Based Chemotherapy

et al. 2018

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Progressive multifocal leukoencephalopathy (pml) is a rare demyelinating disease of the central nervous system that most often affects immunocompromised individuals. It is caused by the reactivation of the John Cunningham virus (jcv), which is found in latent form in the majority of adults. We describe a 59-year-old man with multiple myeloma who developed severe neurological deficits during treatment with ixazomib-based chemotherapy. A diagnosis of pml was established with gadolinium-enhanced magnetic resonance imaging (mri) and by detection of jcv in the cerebrospinal fluid. Despite cessation of chemotherapy and treatment with mirtazapine, he had an inexorable neurological decline and died two months after presenting to hospital. Multiple myeloma and its treatments can predispose patients to opportunistic infections including pml. Although there have been case reports of pml in patients with multiple myeloma treated with bortezomib (a different proteosome inhibitor), this is, to our knowledge, the first documented case of pml in a patient treated with a regimen that includes ixazomib.

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“…Based on Younis's work comparing the sensitivity of liver function classification systems for exposure changes, the NCI scale appears to be the most precise for indicating exposure changes in hepatically impaired cancer patients [13] . Multiple studies have used the NCI scale to classify cancer patients according to the degree of hepatic impairment and to inform dosing recommendations in these subpopulations [14][15][16][17] . Recently, the FDA suggested using the NCI scale as an alternative to the Child-Pugh scale for hepatic impairment classification in oncology trials [18] .…”

Section: Classification Of Hepatic Impairmentmentioning

confidence: 99%

A Review of Regulatory Guidance for Conducting Hepatic Impairment Studies: A Case Study in Oncology

Lin¹,

D’Cunha²

2018

JOCR

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Running Title: Review of regulatory guidance for hepatic impairment studies ABSTRACTThe liver is a vital organ that plays a central role in the metabolism and elimination of drug molecules. Impairment of this vital organ can lead to increased accumulation of parent drug or active metabolites, affecting systemic drug disposition, clinical efficacy, safety and tolerability. Hepatic disease in cancer patients is generally associated with the metastatic spread of the primary tumor to or near the liver, or by toxicities associated with treatment using chemotherapeutic agents. Over the last decade, the understanding of cancer has changed the field of drug development and has resulted in novel, oral targeted therapies that interfere with dysregulated pathways in cancer. Many of these orally administered agents are dependent on the liver for drug metabolism and so understanding hepatic impairment in cancer is imperative to achieve appropriate dose adjustments and to avoid toxicity. This mini-review will focus on how published guidance from the US Food & Drug Administration (FDA) and European Medicines Agency (EMEA) on hepatic impairment studies can be tailored to guide study design and subsequent dosage modification in cancer patients with varying degrees of hepatic dysfunction.

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Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment

Cited by 40 publications

References 22 publications

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

Progressive Multifocal Leukoencephalopathy during Ixazomib-Based Chemotherapy

A Review of Regulatory Guidance for Conducting Hepatic Impairment Studies: A Case Study in Oncology

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