High-flux hemodialysis versus glucarpidase for methotrexate-associated acute kidney injury: What’s best?

Kitchlu, Abhijat; Shirali, Anushree C.

doi:10.1177/2399369319827305

Cited by 10 publications

(9 citation statements)

References 46 publications

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“…Methotrexate (MTX) is an antineoplastic agent, usually administered alone or as part of a combined chemotherapy regimen. In some prevalent cancers like non-Hodgkin lymphoma, acute lymphoblastic leukaemia (ALL) and osteosarcoma, MTX is used at high-doses (> 500 mg/ m 2 ) [1][2][3][4][5][6] MTX doses and infusion times depend on diagnosis and patient conditions (e.g. paediatric or adult patient), ranging from 0.5-5 g/m 2 in 4-36 h in ALL patients to 8-12 g/m 2 in 4 h in osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study

Gros

Pérez

Cabero-Martínez

et al. 2022

J Oncol Pharm Pract

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Introduction High-dose methotrexate (HDMTX) is administered for the treatment of some cancers. HDMTX is usually safe but may crystallize in renal tubules causing acute kidney injury (AKI). Consequently, MTX elimination is delayed, resulting in a severe and life-threatening condition. No studies have been published about the impact of MTX toxicity in Spain. This study aims to estimate the incidence and management of MTX delayed elimination and toxicity. Methods A two-round Delphi study was performed to reach consensus between 10 medical experts on haemato-oncology and paediatric oncology with experience in the management of HDMTX treated patients from leading Spanish hospitals. An online questionnaire was developed based on national and international guidelines and previous evidence regarding HDMTX-related toxicity. Consensus was established at 80% agreement. Median and interquartile ranges were calculated, and incidence data were extrapolated to the Spanish general population. Results Out of 1.475 patients estimated to receive HDMTX treatment annually in Spain, 27.5% present MTX delayed elimination and 11.6% develop HDMTX-induced AKI (35.4% with severe systemic toxicities (>grade 3) and 18.8% develop chronic renal disease). Mortality is estimated in 4.2%. Immuno-enzymatic assay is used in most of the hospitals (90%) for MTX serum level monitoring. All experts use increased supportive care and high leucovorin as first-line treatment. Available treatments in experts’ hospitals in case toxicity persists are haemodialysis (90% of hospitals), glucarpidase (60%) and hemofiltration (50%). Most prevalent non-renal systemic toxicities are haematologic and mucositis (21–40% of patients). Patients with HDMTX-induced AKI require from intensive care (5% of patients), more than 3 sessions and 4 days of dialysis, and about 8.5 days of hospitalization (non-ICU patients) and 12 days in case of patients requiring ICU. Conclusions These results are the first evidence regarding HDMTX-induced AKI in Spain. Incidence and mortality results are in line with previous studies. Clinical management is based on preventive measures and the treatment depend on the availability in the hospital. The need for effective, safe and rapid treatment for the reduction of MTX toxic levels and the improvement of monitoring methods were noted by experts as urgent needs. Further observational studies to validate these results would be needed.

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Section: Introductionmentioning

confidence: 99%

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study

Gros

Pérez

Cabero-Martínez

et al. 2022

J Oncol Pharm Pract

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“…The second category includes intermediate IV doses ranging from 100–500 mg/m 2 (3.3–16.6 mg/kg) and are designated for breast and other solid tumors, as well as low-grade leukemias and lymphomas. The final category includes high-dose MTX, defined as a dose greater than or equal to 500 mg/m 2 (HDMTX ≥16.6 mg/kg), that is the mainstay IV chemotherapy for primary central nervous system lymphoma, osteosarcoma, and high-grade leukemias/lymphomas such as non-Hodgkin lymphoma; these treatment regimens are administered over several days [ 25 – 27 ]. Accordingly, we decided to administer a HDMTX treatment to WT mice for seven consecutive days in our present investigation as it is in line with the dosage employed in the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Efficiency of antioxidant Avenanthramide-C on high-dose methotrexate-induced ototoxicity in mice

et al. 2022

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Methotrexate (MTX) has been used in treating various types of cancers but can also cause damage to normal organs and cell types. Folinic acid (FA) is a well-known MTX antidote that protects against toxicity caused by the drug and has been used for decades. Since hearing loss caused by MTX treatment is not well studied, herein we aimed to investigate the efficiency of the antioxidant Avenanthramide-C (AVN-C) on high-dose MTX (HDMTX) toxicity in the ear and provide insights into the possible mechanism involved in MTX-induced hearing loss in normal adult C57Bl/6 mice and HEI-OC1 cells. Our results show that the levels of MTX increased in the serum and perilymph 30 minutes after systemic administration. MTX increased hearing thresholds in mice, whereas AVN-C and FA preserved hearing within the normal range. MTX also caused a decrease in wave I amplitude, while AVN-C and FA maintained it at higher levels. MTX considerably damaged the cochlear synapses and neuronal integrity, and both AVN-C and FA rescued the synapses. MTX reduced the cell viability and increased the reactive oxygen species (ROS) level in HEI-OC1 cells, but AVN-C and FA reversed these changes. Apoptosis- and ROS-related genes were significantly upregulated in MTX-treated HEI-OC1 cells; however, they were downregulated by AVN-C and FA treatment. We show that MTX can cause severe hearing loss; it can cross the blood–labyrinth barrier and cause damage to the cochlear neurons and outer hair cells (OHCs). The antioxidant AVN-C exerts a strong protective effect against MTX-induced ototoxicity and preserved the inner ear structures (synapses, neurons, and OHCs) from MTX-induced damage. The mechanism of AVN-C against MTX suggests that ROS is involved in HDMTX-induced ototoxicity.

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“…However, hemodialysis typically requires multiple sessions, extends inpatient stay, may lead to severe complications, and can be followed by a rebound in MTX levels. 1,9 Glucarpidase (Voraxaze ® , BTG International Inc.) is a recombinant carboxypeptidase that rapidly reduces plasma MTX concentration by hydrolyzing MTX into two inactive metabolites. 8 Administered intravenously, glucarpidase can substantially lower the plasma MTX concentration by 97% within 15 minutes, independent of renal clearance, with 91% of patients sustaining MTX reduction for up to 8 days.…”

Section: Introductionmentioning

confidence: 99%

“…A recent consensus guideline for the stocking of antidotes in emergency departments recommended that hospitals should stock glucarpidase, 18 but this is not routinely done by many institutions. 9 There may be hesitancy, or funding restrictions, around acquiring and prescribing glucarpidase due to its cost. 9,19 However, there have been no published economic analyses to evaluate the cost-effectiveness or https://doi.org/10.2147/CEOR.S397154…”

Section: Introductionmentioning

confidence: 99%

Glucarpidase for Treating Adults with Delayed Methotrexate Elimination Due to Impaired Renal Function: An Economic Simulation Analysis

Kala¹,

Nelson²,

Drudge³

et al. 2023

CEOR

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Background: Glucarpidase is indicated for treating delayed methotrexate (MTX) elimination due to impaired renal function. Although glucarpidase is capable of rapidly eliminating MTX independent of renal clearance, its cost can be perceived as a barrier to use. However, no published economic analyses have evaluated glucarpidase relative to comparable treatments. Purpose: To assess the economic value of glucarpidase for treating adult patients in the United States (US) who experience delayed MTX elimination due to impaired renal function. Methods: A decision tree model was developed to assess the economic value of glucarpidase. The short-term inpatient management of patients as well as long-term survival were simulated. Costs associated with the use of glucarpidase were compared against other methods for treating delayed MTX elimination due to impaired renal function under two scenarios: current practice (ie, mix of timely/ delayed use of glucarpidase, hemodialysis, or supportive care [SC] alone) as compared with proposed practice (ie, timely glucarpidase administration within 60 hours for all eligible patients). Hypothetical practical scenarios for US institutions were also considered. Results: For adult patients with delayed MTX elimination, proposed practice as compared to current practice was associated with an increased cost of $20,024 per patient, not considering any incremental reimbursement associated with glucarpidase administration. Importantly, early treatment with glucarpidase, within 60 hours, was shown to be less expensive per patient than delayed glucarpidase treatment or treating with hemodialysis, but more expensive than SC alone. However, proposed practice was associated with multiple clinical benefits, including shorter hospital length of stay. For hypothetical practical scenarios, minimal shifts in treatment patterns had minimal cost impacts. Conclusion:Treatment of all eligible patients with glucarpidase within 60 hours was associated with an increased cost per patient (relative to current practice) but substantial improvements in clinical outcomes. Timely glucarpidase use was less expensive than delayed glucarpidase or hemodialysis.

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High-flux hemodialysis versus glucarpidase for methotrexate-associated acute kidney injury: What’s best?

Cited by 10 publications

References 46 publications

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study

Efficiency of antioxidant Avenanthramide-C on high-dose methotrexate-induced ototoxicity in mice

Glucarpidase for Treating Adults with Delayed Methotrexate Elimination Due to Impaired Renal Function: An Economic Simulation Analysis

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