Administration Of Glucarpidase Research Articles

Early therapeutic drug monitoring of methotrexate and its association with acute kidney injury: A retrospective cohort study.

High-dose methotrexate (HDMTX) use can be limited by the development of acute kidney injury (AKI). Early AKI detection is paramount to prevent further renal injury and irreversible toxicities. This study sought to determine whether early elimination patterns of MTX would be useful as a biomarker of AKI in HDMTX treatment. This retrospective cohort study included two sites that collected ≥2 MTX levels within 16 h from completion of MTX infusion. Early levels were tagged and MTX elimination half-life (t½) were calculated from combinations of two of three different early time periods. Receiver operating characteristic (ROC) curves were synthesized for each elimination t½ (biomarker) with respect to AKI and delayed methotrexate elimination (DME); the biomarker with the highest area under the ROC curve (AUC) was tested in a multiple variable logistic regression model. Data from 169 patients who received a total of 556 courses of HDMTX were analyzed. ROC analysis revealed MTX elimination t½ calculated from the second and third time periods had the highest AUC for AKI at 0.62 (interquartile range [IQR] 0.56-0.69) and DME at 0.86 (IQR 0.73-1.00). After adjusting for age, sex, dose (mg/m2), infusion duration, HDMTX course, and baseline estimated glomerular filtration rate, it remained significant for AKI with an OR of 1.29 and 95% confidence interval of 1.03-1.65. Early MTX elimination t½ measured within 16 h of infusion completion was significantly associated with the development of AKI and serves as an early clearance biomarker that may identify patients who benefit from increased hydration, augmented leucovorin rescue, and glucarpidase administration.

Phase 2 study of glucarpidase in patients with delayed methotrexate elimination after high-dose methotrexate therapy

PurposeHigh-dose methotrexate therapy (HD-MTX) is a standard treatment for various malignant tumors, but approximately 1–10% of patients experience delayed MTX elimination (DME) that can induce organ damage. Glucarpidase can hydrolyze MTX and thereby lower the level of active MTX in the blood. A multicenter, open-label, phase II investigator-initiated trial (CPG2-PII study) was conducted to evaluate glucarpidase rescue therapy in Japanese patients who showed DME after HD-MTX treatment. To confirm the robustness of this therapy, further corporate-sponsored clinical trial (OP-07-001 study) was conducted.MethodsThe primary endpoint in the CPG2-PII study was to evaluate the proportion of patients of the percentage clinical important reduction (CIR) as an indicator of MTX concentration, which can be managed with leucovorin and supportive care. The primary endpoint of the OP-07-001 study was to evaluate the decreasing rate of plasma MTX concentration at 20 min after glucarpidase administration from the baseline for four patients. Glucarpidase was administered at a dose of 50 U/kg for 15 and 4 patients, respectively in the two studies, and safety was analyzed for each of them.ResultsThe rate of CIR was 76.9% (95% confidence interval, 46.2–95.0%) in the CPG2-PII study. The median reduction rate of plasma MTX was 98.83% in the OP-07-001 study. Hypersensitivity, blood bilirubin increased, and headache for each patient were the only study drug-related events.ConclusionGlucarpidase showed an effect of reducing plasma MTX concentration in Japanese patients with DME as that observed in a previous US study, confirming its favorable safety and tolerability.

Rechallenge With High-Dose Methotrexate After Treatment With Glucarpidase in Adult Patients With Lymphoma.

Limited evidence exists regarding methotrexate (MTX) resumption after patients with lymphoma receive glucarpidase for toxic MTX levels and acute kidney injury (AKI). This retrospective review included adults with lymphoma treated with glucarpidase after MTX at Mayo Clinic between January 31, 2020, and October 10, 2022. Descriptive statistics summarize patient characteristics and clinical outcomes. Of 11 patients treated with glucarpidase after MTX, seven (64%) were rechallenged with MTX. Indications for MTX rechallenge included confirmed CNS disease (n = 6, 86%) and intravascular lymphoma (n = 1, 14%). Compared with the nonrechallenged subgroup, before receiving MTX that required glucarpidase rescue, the rechallenged patients had lower median pretreatment serum creatinine (Scr; 0.7 v 1.2 mg/dL), and none had AKI with previous MTX doses, n = 0 (0%) versus n = 2 (50%). During the MTX dose requiring glucarpidase rescue, the rechallenged group had lower median peak Scr (1.26 v 3.32 mg/dL) and lower incidence of AKI stage III (n = 1 [14%] v n = 3 [75%]), and none of the rechallenged patients required renal replacement therapy (RRT; n = 0 [0%] v n = 1 [25%]). At the first rechallenge after glucarpidase administration, the median MTX dose reduction was 56% (range, 46%-75%), and the lowest used dose when prescribed according to each treatment protocol schedule was 1.5 g/m2. Two (29%) patients experienced AKI (n = 1 stage I, n = 1 stage II) after MTX rechallenge. Zero patients required RRT, and zero required another glucarpidase administration. Six (86%) patients completed all recommended MTX doses. In selected adults with lymphoma who required glucarpidase for toxic MTX levels after administration of high-dose MTX, resumption of MTX therapy at lower doses is safe. Patients selected for MTX resumption had experienced less severe AKI during the previous cycle compared with those not selected for MTX resumption.

Use of glucarpidase (carboxypeptidase-G2) in pediatric cancer patients: 11-year experience of a tertiary center.

Methotrexate is an essential drug in the treatment of childhood cancer that is not exempt from toxicities. Glucarpidase is a drug used to reduce the toxic concentration of plasma methotrexate in patients with delayed elimination or at risk of toxicity. We describe the characteristics of a cohort of pediatric patients that received glucarpidase and analyze its role in the treatment of toxicity induced by high doses of methotrexate (HDMTX). Retrospective observational study of all pediatric cancer patients who received glucarpidase between 2012 and 2022 at a single center. Fifteen patients were treated with a single dose of glucarpidase, eleven of them presented with acute lymphoblastic leukemia and received HDMTX at 5g/m2 in 24-hour infusion. In eight patients, glucarpidase was administered during the first cycle of HDMTX. The indication in thirteen cases was acute renal failure with delayed elimination of plasma methotrexate. The median maximum creatinine was 1.22mg/dl (0.682.01mg/dl), with a median increase over its baseline level of 313%. All patients normalized renal function after glucarpidase administration, with a median methotrexate excretion time of 193 hours (42-312hours). No grade ≥2 adverse events derived from carboxypeptidase administration. Eleven patients received new doses of HDMTX in subsequent cycles, without new episodes of serious toxicity. The use of glucarpidase is effective and safe in the treatment of acute renal failure and methotrexate elimination delay in pediatric cancer patients. Further HDMTX doses may be prescribed without additional toxicities.

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

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. 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. 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. 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. 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.

CTNI-61. PILOT STUDY OF REPEATED PLANNED GLUCARPIDASE FOLLOWING HIGH DOSE METHOTREXATE (HD-MTX) IN CNS LYMPHOMA (CNSL)

Abstract This study explores the repeated use of glucarpidase following HD-MTX in patients with CNSL. HD-MTX requires aggressive hydration and inpatient monitoring to prevent toxicity. Glucarpidase 50 units(u)/kg for delayed MTX clearance results in a reduction of systemic MTX levels without crossing the blood brain barrier. This study explores the use of 1000 or 2000 units of glucarpidase following repeated cycles of MTX 3–8 g/m2. Eligible adult patients had isolated CNSL, CrCl ≥ 60 mL/min, and KPS ≥ 50. Rituximab with MTX was administered for eight cycles. Glucarpidase was given 24 hours after each MTX infusion. MTX concentrations were monitored in serum and cerebrospinal fluid (CSF). Twelve patients enrolled to date and data are available for 50 doses of MTX (3 g/m2 (20), 6 g/m2 (21), 8 g/m2 (9)). Glucarpidase 1000u (14) or 2000u (36) resulted in at least a 95% reduction in serum MTX levels within 15 minutes following 49/50 doses. A 93% decrease was seen with the remaining dose. Glucarpidase was not detected in the CSF of 7 patients analyzed. Potentially cytotoxic MTX concentrations (10–6 M) were observed in CSF 1 hour (7/7) and 6 hours (4/7) after glucarpidase administration. Radiographic responses are evaluable in 9 patients: complete response (5), partial response (2), stable disease (1), and progressive disease (1). No grade 3 events were attributed to glucarpidase; one grade 4 event of anaphylaxis occurred. Anti-glucarpidase antibodies were detected in 2/5 patients analyzed. In summary, administration of low-dose glucarpidase 24 hours after MTX 3–8 g/m2 results in a reproducible rapid reduction in serum MTX levels in non-renally impaired patients. CSF MTX levels remain therapeutic and clinical response expected from MTX-based therapy does not appear compromised. Anti-glucarpidase antibodies may develop though significance remains unclear. Study is ongoing. Future directions will explore glucarpidase use for reduction of inpatient stay with HD-MTX.

MTXPK.org: A Clinical Decision Support Tool Evaluating High-Dose Methotrexate Pharmacokinetics to Inform Post-Infusion Care and Use of Glucarpidase.

Methotrexate (MTX), an antifolate, is administered at high doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high‐dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life‐threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 SDs above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of laboratory results that do not directly correspond to the algorithm prove to be a limitation of its use. The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel 3‐compartment MTX population pharmacokinetic (PK) model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web‐based tool has the functionality to utilize individualized demographics, serum creatinine, and real‐time drug concentrations to predict the elimination profile and facilitate model‐informed administration of glucarpidase.

Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance.

Glucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high-dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication on the label does not give specific methotrexate concentrations above which it should be used. An international group of experts was convened to develop a consensus guideline that was specific and evidence-based to identify the population of patients who would benefit from glucarpidase.

Practical considerations for the administration of glucarpidase in high-dose methotrexate (HDMTX) induced renal dysfunction.

Pediatric Blood & CancerVolume 62, Issue 9 p. 1512-1513 Highlight Practical considerations for the administration of glucarpidase in high-dose methotrexate (HDMTX) induced renal dysfunction Brigitte C. Widemann MD, Corresponding Author Brigitte C. Widemann MD Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland Correspondence to: Brigitte Widemann, Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 1-5750, Bethesda, MD 20892. E-mail: widemanb@mail.nih.govSearch for more papers by this author Brigitte C. Widemann MD, Corresponding Author Brigitte C. Widemann MD Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland Correspondence to: Brigitte Widemann, Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 1-5750, Bethesda, MD 20892. E-mail: widemanb@mail.nih.govSearch for more papers by this author First published: 04 May 2015 https://doi.org/10.1002/pbc.25577Citations: 5 Conflict of interest: Nothing to declare. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume62, Issue9September 2015Pages 1512-1513 RelatedInformation

Efficacy of Glucarpidase (Carboxypeptidase G2) in Patients with Acute Kidney Injury After High‐Dose Methotrexate Therapy

Because the incidence rate of renal impairment is 2-10% for patients treated with high-dose methotrexate and renal impairment develops in 0-12.4% of patients treated for osteosarcoma, we sought to evaluate the efficacy of glucarpidase, a recently approved drug that rapidly hydrolyzes methotrexate to inactive metabolites, which allows for nonrenal clearance in patients with delayed renal methotrexate elimination. Pooled analysis of efficacy data from four multicenter single-arm compassionate-use clinical trials using protocols from 1993 to 2007. Of 476 patients with renal toxicity and delayed methotrexate elimination who were treated with intravenous glucarpidase for rescue after high-dose methotrexate, 169 patients had at least one preglucarpidase (baseline) plasma methotrexate concentration greater than 1μmol/L and one postglucarpidase methotrexate concentration measurement by high-performance liquid chromatography and were included in the efficacy analysis; renal recovery was assessed in 436 patients who had at least one recorded preglucarpidase and postglucarpidase serum creatinine concentration measurement. Efficacy was defined as rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, with a concentration of 1μmol/L or lower at all postglucarpidase determinations. Median age of efficacy-evaluable patients was 20years (range 5weeks-84years). Osteosarcoma (36%), non-Hodgkin lymphoma (27%), and acute lymphoblastic leukemia (20%) were the most frequent underlying diagnoses. Median preglucarpidase serum methotrexate was 11.7μmol/L. At the first (median 15minutes) through the last (median 40hours) postglucarpidase measurement, plasma methotrexate concentrations demonstrated consistent 99% median reduction. RSCIR was achieved by 83 (59%) of 140 patients. A total of 64% of patients with renal impairment greater than or equal to Common Terminology Criteria for Adverse Events grade 2 recovered to grade 0 or 1 at a median of 12.5days after glucarpidase administration. Glucarpidase caused a clinically important 99% or greater sustained reduction of serum methotrexate levels and provided noninvasive rescue from methotrexate toxicity in renally impaired patients.

Leucovorin (LV) pharmacokinetics in patients receiving high dose methotrexate (HDMTX), with or without glucarpidase treatment.

e20521 Background: Glucarpidase is a recombinant form of carboxypeptidase G2 and hydrolyzes MTX into inactive metabolites and provides alternate clearance in pts with delayed elimination and acute kidney injury. It is administered with IV hydration, urinary alkalinization, and LV. The primary objective was to investigate whether glucarpidase reduces exposure to LV and its active metabolite (5EMeTHF) to below the level achieved in pts who have not received glucarpidase, by assessing the PK of the active L-isomer of LV (6S-LV) following administration of HDMTX and LV. Methods: Open-label, multicenter PK study in pts treated with HDMTX (≥1 g/m2) and LV (either ≥15 mg or ≥10 mg/m2) with subsequent glucarpidase where indicated for renal impairment (Arm A) or without glucarpidase (Arm B). Plasma samples for LV and 5EMeTHF were taken pre-LV and at 5, 30, 60, 120, and 180 min after LV to calculate the area under the concentration curve of 6S-LV over 0-3 hours (AUC0-3) following the LV dose. Results: 17 pts (8 Arm A, 9 Arm B) were analyzed. The median pre-glucarpidase methotrexate (MTX) plasma concentration was higher for Arm A 7.5 µmol/L) than B (1.1 µmol/L). Similarly, median LV doses were 89.88 mg/m2 (Arm A) and 13.51 mg/m2(Arm B). Mean 6S-LV AUC0-3 values (µmol*h/L) for Arm A were 8.70±5.56, compared with 1.31±0.78 for Arm B, consistent with Arm A receiving a higher LV dose than Arm B. Mean 6S-5MeTHF AUC0-3 values (µmol*h/L) were similar in arms A and B (0.68 and 0.73). When normalized for LV doses, mean 6S-LV AUC0-3values (µmol*h/L) were similar between arms:10.02±4.83 in Arm A versus 9.79±5.18 for Arm B. Conclusions: Glucarpidase does not reduce exposure to 6S-LV and 5-MeTHF to below the level achieved in patients with normal renal function who did not receive glucarpidase. Adequate LV exposure is achieved if LV dosing is based on pre-glucarpidase plasma MTX concentration for at least 48 hours after glucarpidase administration. Clinical trial information: NCT00634504.

GRP-111 Management of Methotrexate-Induced Renal Failure Without Glucarpidase

BackgroundGlucarpidase (Voraxaze) is effective in the treatment of methotrexate (MTX)-induced renal dysfunction but many cases this can be handled with standard treatment.PurposeTo describe the progress of a patient with MTX-induced...

A Phase 1 Trial of Escalating High Dose Methotrexate Supported by Glucarpidase to Treat Patients with Primary Central Nervous System Lymphoma (PCNSL). (CRUK/08/010)

AbstractAbstract 4850 BackgroundMethotrexate (MTX) remains the most important drug in the treatment of PCNSL but has considerable toxicities and is dose-limited by renal function. Glucarpidase (Voraxaze®) is an enzyme, which rapidly hydrolyses MTX and is licensed in the United States for the treatment of toxic levels of MTX in patients with delayed excretion due to impaired renal function. We designed this trial to investigate whether pre-emptive administration of glucarpidase after MTX infusion might allow safer therapy and allow higher doses to be given without increased toxicity. MethodsNewly diagnosed PCNSL patients aged ≥18yrs would be entered into 3 successive, dose escalating cohorts. Patients would receive an increasing MTX dosage (3, 5 and 10 grams/m2 according to their cohort). They would receive up to 6 cycles of single agent MTX at their cohort dose level with an MRI assessment every 2 cycles. All cycles were pre-emptively supported by the administration of glucarpidase. This was followed by whole brain radiotherapy (WBRT) tailored to age and fitness. MTX was infused over 4 hours and glucarpidase was given 22 hours from the start of the MTX infusion at a dose of 50units/Kg over 15mins. MTX levels were measured pre + post glucarpidase and at 48 and 72 hours post MTX. Further levels were taken if required. Standard fluids, alkalinisation and folinic acid rescue was used in addition. MTX levels were measured locally to guide clinical decisions and centrally by HPLC to assess true clearance as there is cross-reactivity between MTX and the metabolites to which it is cleaved by Glucarpidase, making routine assays inaccurate as they may include metabolites and thus give a falsely high reading. The first cohort consisting of 6 patients would receive 3g/m2 MTX per cycle. Using the modified Fibonacci scheme, the intention was to escalate to 6g/m2 (2 × starting dose) and then 10 g/m2 (3.3 × starting dose) in 2 subsequent cohorts. If 2 patients have dose limited toxicity (DLT), the escalations are stopped. Each cohort would commence after the preceding one has completed at least 2 cycles of MTX. ResultsThe trial stopped after recruiting 4 patients in cohort 1 due to 2 patients experiencing DLT. The patients were 2 male and 2 female, aged between 51 and 71yrs, all HIV negative and histologically confirmed as DLBCL by brain biopsy. In total, ten assessable cycles of MTX (3g/m2) with no dose reductions were delivered to these 4 patients. There were toxicity delays in 3 cycles.There were 38 adverse events (6 > grade 2) and 8 serious adverse events, 2 of which were DLTs in separate patients and led to the closure of the study as per protocol rules. The two DLTs were renal impairment with delayed MTX excretion in one patient following their 1st cycle of MTX and repeated renal pain/urinary retention alongside grade 2 infusion reactions to glucarpidase in the other. The patient with renal impairment had normal baseline renal function but experienced a creatinine rise 48hrs after the start of the MTX infusion and peaking at 269μmoles/l. by day 6. This remained elevated for 21 days before returning to normal. One patient had infusion reactions to glucarpidase of grade 2 severity with each of 3 cycles received despite a dose reduction in cycle 3. The development of antibodies to glucarpidase was demonstrated in 2 patient samples but there was no evidence of neutralising potential.The central HPLC assays did indeed confirm rapid MTX clearance by the enzyme in all 10 cycles, with levels of MTX 1 hour post glucarpidase at or near the clinical cut-off (0.05μmol/L) and no levels above this at 48 hours from the start of the MTX infusion. As expected, local assays were less reliable - for example the patient with renal injury cleared their MTX (judged by HPLC) rapidly but the local assays continued to show apparent delayed clearance over nearly 2 weeks. Discussion and ConclusionsIn summary, used pre-emptively, Glucarpidase was well tolerated and achieved the expected rapid reduction in MTX levels, however, HPLC is required to demonstrate this in real time as hospital laboratory monitoring suffers from metabolite interference. It was not possible to escalate MTX doses in this protocol, most likely due to the nature of the patient population. The occurrence of an acute renal injury in this setting suggests that the damage may occur early at the point of high (therapeutic) MTX serum levels, which may not be wholly prevented by subsequent rapid clearance of residual drug by Glucarpidase. Disclosures:Off Label Use: This study is of an unlicensed use of a licensed product. The product (glucarpidase) is licensed for the prevention of toxicity when there is renal impairment post methotrexate administration but this study investigated its use as pre-emptive therapy for preventing toxicity in a single setting (primary central nervous system lymphoma).

Clinical trial and compassionate use experience with glucarpidase for methotrexate toxicity.

6530 Background: High dose methotrexate (MTX) is used to treat acute lymphoblastic leukemia (ALL), osteogenic sarcoma, non-Hodgkin lymphoma (NHL), and other cancers. MTX-associated renal impairment with delayed MTX elimination develops after 2 to 10% of treatment cycles, exposing patients to elevated MTX concentrations with potential for enhanced MTX toxicity and prolonged hospitalization. Glucarpidase, a recombinant form of carboxypeptidase G2, rapidly hydrolyzes MTX into inactive metabolites and provides an alternate way of clearance in patients with delayed MTX elimination. Methods: From November 1993 to June 2009, 492 patients experiencing renal toxicity and delayed elimination of MTX were treated with glucarpidase (50 U/kg intravenously) in compassionate use trials conducted in the US and EU. Their outcomes are presented here. Results: The median age of the 492 patients was 18 yrs (range: 5 wks to 85 yrs). Sixty-three percent were male. Forty-one percent had NHL, 30% osteogenic sarcoma, 23% ALL, and 7% other malignancies. The median pre-glucarpidase MTX concentration was 17 µmol/L. Seventy-six percent of patients received 1 dose of glucarpidase, 22% received 2 doses, and 2% received 3 doses. The first dose of glucarpidase was given at a median of 3 days after MTX administration. One-hundred and fifty-six patients had MTX concentrations determined by HPLC. At the first measurement (median 15 minutes post-glucarpidase) MTX was reduced by a median of 99% relative to the pre-glucarpidase baseline. At the last measurement (median 40 hrs post-glucarpidase) median MTX reduction remained at 99% compared with baseline. In 410 patients with pre-glucarpidase renal impairment measured as CTCAE Grade 2 or higher, 64% recovered to Grade 0 or 1 after a median of 12.5 days post-glucarpidase. Glucarpidase was well-tolerated overall; adverse events included paresthesia (2.0%), flushing (1.8%) and headache (1.0%). Eight percent of patients died within 30 days of glucarpidase administration of causes unrelated to glucarpidase, as judged by the treating physician. Conclusions: Glucarpidase is well-tolerated and reduces MTX concentrations by 99% within 15 min of administration in patients with impaired renal clearance of MTX.

Monitoring of methotrexate levels following glucarpidase rescue treatment requires detection by mass spectrometry since immunoassay is not applicable

BackgroundPatients treated with high-dose methotrexate may experience severe toxicity when excretion is delayed if acute renal dysfunction develops. Potentially lethal toxicity may be limited by hydration, alkalisation and administration of...

Glucarpidase: Treatment for toxic MTX concentrations

Glucarpidase: Treatment for toxic MTX concentrations

Glucarpidase to combat toxic levels of methotrexate in patients

In January 2012, glucarpidase (Voraxaze®) received approval from the US Food and Drug Administration for intravenous treatment of toxic plasma methotrexate concentrations due to impaired renal clearance. Methotrexate, an antifolate agent, has been used for over 60 years in the treatment of various cancers. High-dose methotrexate has been particularly useful in the treatment of leukemias and lymphomas. However, even with aggressive hydration and urine alkalinization, such regimens can lead to acute renal dysfunction, as indicated by decreases in urine production and concomitant increases in blood urea nitrogen and serum creatinine levels. Because methotrexate is largely excreted by the kidneys, this can greatly potentiate tissue damage. Toxic levels of blood methotrexate can be rapidly and effectively decreased by intravenous administration of glucarpidase. Glucarpidase is a recombinant form of carboxypeptidase G2, a bacterial enzyme that rapidly cleaves methotrexate to form the amino acid glutamate and 2,4-diamino-N10-methylpteroic acid. Catabolites of methotrexate are much less toxic than the parent compound, and are primarily excreted by hepatic mechanisms. Glucarpidase has been available on a compassionate basis since the 1990s, and a variety of case reports and larger clinical trials have demonstrated the safety and efficacy of this drug in patients ranging in age from infants to the elderly and in a variety of races and ethnic groups. Glucarpidase should not be administered within 2 hours of leucovorin, because this agent is a reduced folate which competes with methotrexate for the enzyme and glucarpidase inactivates leucovorin. Side effects of glucarpidase are rare and relatively mild, and include paraesthesia, flushing, nausea, vomiting, pruritus, and headache. Glucarpidase has seen limited use in intrathecal treatment of methotrexate toxicity for which it is also effective. Future applications of this enzyme in chemotherapy continue to be an active area of research.

High-Dose Methotrexate-Induced Renal Dysfunction: Is Glucarpidase Necessary for Rescue?

TO THEEDITOR: Widemann et al 1 report the use of glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction. When patients develop delayed excretion of methotrexate and impaired renal function after the administration of high-dose methotrexate there are two equally important imperatives. First, we must protect the patients from the potential toxicity of prolonged exposure to the antifolate drug methotrexate. Potential toxicities include myelosuppression, mucositis, and hepatoxicity, and can be lethal. The second imperative is to have the patient’s renal function return to normal to allow continuation of the chemotherapy needed to treat the underlying malignancy. The authors performed an analysis to determine which factors predicted greater than or equal to grade 4 toxicity. They noted that inappropriate increase in leucovorin predicted perfectly for development of greater than or equal to grade 4 toxicity and therefore could not be included in their multiple factor logistic regression analysis. We have reported our experience treating patients who have delayed methotrexate excretion and renal failure after high-dose methotrexate administration using high-dose leucovorin as the sole form of rescue. 2 All patients in our experience were salvaged. None of our patients died. The authors report that the median time to recovery of renal function for their cohort was 22 days. Our experience, albeit considerably smaller, achieved at least as good a time to recovery of normal renal function. One possible interpretation of the results that the authors report is that glucarpidase was not an essential component of rescue for patients experiencing high-dose methotrexate-related renal dysfunction and that similar results could have been achieved with the use of high-doses of leucovorin alone. Glucarpidase is unquestionably an excellent way to lower the plasma methotrexate concentration. This effect, however, has no impact on intracellular concentrations of methotrexate or on renal function. Protection of cells from intracellular methotrexate still requires the administration of high-doses of leucovorin and renal recovery appears to take place independently of glucarpidase administration. The authors’ conclusion that early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop high-dose methotrexate-related renal dysfunction may be true but the authors should consider the possibility that similar results could be achieved with leucovorin alone.

Glucarpidase, Leucovorin, and Thymidine for High-Dose Methotrexate-Induced Renal Dysfunction: Clinical and Pharmacologic Factors Affecting Outcome

To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

Treatment of Methotrexate Intoxication with Various Modalities of Continuous Extracorporeal Therapy and Glucarpidase

Methotrexate, administered for treatment of pediatric and adult malignancies, is a direct renal toxin, which can lead to renal dysfunction, decreased methotrexate clearance, elevated methotrexate concentrations, and systemic toxicity. Although plasma methotrexate concentrations have been shown to decline precipitously after a single dose of glucarpidase, this drug is investigational and available only through compassionate use. Therefore, alternative treatments for methotrexate removal may be required. We describe a 13-year-old girl (body surface area 1.2 m(2)) with osteosarcoma who was treated with high-dose methotrexate 12 g/m(2) infused over 4 hours. Forty-eight hours after the infusion, her plasma methotrexate concentrations were elevated at 446 micromol/L. She exhibited severe signs of methotrexate toxicity, including encephalopathy, liver failure, and acute kidney injury, and could not tolerate conventional hemodialysis. Over the next 12 days, the patient was treated with continuous venovenous hemodialysis (CVVHD), single-pass albumin dialysis (SPAD), continuous venovenous hemodiafiltration (CVVHDF), and glucarpidase to enhance methotrexate elimination. Compared with standard CVVHD, SPAD did not significantly increase methotrexate removal as measured by elimination half-life and methotrexate saturation coefficient. The highest clearance rate among extracorporeal therapies was achieved by CVVHDF, with an effluent rate of 4950 ml/hour. The patient's clinical condition steadily improved, and all extracorporeal therapies were stopped 168 hours after methotrexate administration. The patient was discharged home and continued with chemotherapy, including methotrexate, which was dosed based on iothalamate glomerular filtration rates on the day before infusion. Although extracorporeal treatments appeared to enhance methotrexate clearance, the administration of glucarpidase resulted in the most rapid percentage decline (86%) in methotrexate concentration. Until glucarpidase is readily available, intermittent hemodialysis should be used to enhance methotrexate clearance. If the patient is unable to tolerate hemodialysis, use of CVVHDF with maximum effluent rates will enhance methotrexate clearance.