Feature: Glucarpidase Dose Capping

Crystal Lu, PharmD, BCOP
Oncology Clinical Pharmacy Specialist
National Institutes of Health, Clinical Center Pharmacy Department
Bethesda, MD

The literature describing reduced-dose glucarpidase is limited to small patient populations, thus institutions and practitioners must weigh the risk versus the benefit of administering doses lower than the FDA-approved dose.
Too much of a good thing? The literature behind alternate glucarpidase dosing strategies.

Background
Methotrexate (MTX) is an antifolate chemotherapy agent that competitively inhibits the enzyme dihydrofolate reductase. It blocks the conversion of dihydrofolate to its active form, thus depleting the intracellular pool of tetrahydrofolates that are required as cofactors for the synthesis of thymidine and purines.¹ MTX doses greater than 500mg/m2 are considered to be high dose (HD) and are indicated to treat adult and pediatric malignancies such as acute lymphoblastic leukemia, osteosarcoma, and lymphomas. High dose MTX-induced acute kidney injury (AKI) is an adverse event that may develop despite appropriate alkalinization, hydration, and leucovorin rescue. Since MTX is primarily eliminated through the kidneys, renal dysfunction delays MTX elimination and results in sustained elevated MTX plasma levels. This life-threatening toxicity puts patients at risk for MTX-related toxicities including myelosuppression, liver dysfunction, and mucositis.^1-3 AKI is reported to occur in up to 12% of patients receiving HDMTX.^4-7

Prior to the U.S. Food and Drug Administration (FDA) approval of glucarpidase, extracorporeal therapies were the primary modalities for removal of serum MTX. However, various methods of dialysis were not very effective due to the highly protein bound nature of MTX at 50% and the tendency for MTX levels to rebound.^8-11 Historically, hemoperfusion/hemodialysis were used to remove serum MTX. The median serum MTX level decreases by 53% following the procedure, but later rebounds 20-90% of pre-dialysis levels. High-flux hemodialysis showed a median decrease of 75% of serum MTX levels and is now the most commonly used method of dialysis for MTX removal.^5,12

Glucarpidase was approved in 2012 for treatment of toxic plasma MTX concentrations (>1 μmol/L) in adult and pediatric patients with delayed MTX clearance due to impaired renal function. Glucarpidase is a recombinant enzyme that hydrolyzes MTX and converts it to inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. This allows for a non-renal pathway of elimination in patients with renal dysfunction.¹³ Consensus guidelines offer more stringent guidance for when to administer glucarpidase depending on the MTX dose, time from MTX infusion, and serum creatinine (Scr) increase from baseline.¹⁴ The Prescribing Information recommends glucarpidase dosing at 50 units/kg as a single intravenous injection.¹³ It is supplied as a lyophilized powder containing 1,000 units per vial. The approximate Average Wholesale Price (AWP) in 2022 is approximately $41,883 per vial.¹⁵ A 70 kg patient’s dose calculates to 3,500 units which will require four vials for compounding and cost $167,532. There is debate whether the manufacturer’s recommendation of 50 units/kg is the optimal dose since dose-finding studies were not performed in humans. More cost-effective approaches have been suggested which include administering less than 50 units/kg, capping the dose at a pre-specified number of vials, or rounding a patient’s dose to a whole vial. We summarize the literature using different glucarpidase dosing strategies in adult and pediatric populations.

Standard glucarpidase dosing in adults and pediatrics
The efficacy of glucarpidase was studied in a subset of 22 patients (12 pediatric and 10 adults) in a single-arm, open-label study. Patients had renal dysfunction and delayed MTX clearance defined as >2 standard deviations greater than the mean excretion curve. Glucarpidase was dosed at 50 units/kg and a second dose was given to patients with pre-glucarpidase MTX concentrations >100 μmol/L. The main outcome measure was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR) in plasma MTX concentration, defined as plasma MTX <1 μmol/L at 15 minutes and sustained up to 8 days. Ten patients (45%) achieved RSCIR and 5 patients (23%) attained a transient plasma MTX concentration <1 μmol/L. These results led to the full FDA approval of glucarpidase in 2012 for delayed MTX clearance due to HDMTX induced AKI.¹³

Alternate dosing strategies in adults
In a multicenter study, Schwartz and colleagues evaluated glucarpidase intervention in adult and elderly patients with delayed MTX elimination. Forty-three patients received the standard 50 units/ kg dose and a second dose was optional in those with serum MTX concentrations >0.1 μmol/L at >24 hours after the first intervention. The median age was 54 years (range 18-78). Investigators saw a >97% reduction in serum MTX by high-performance liquid chromatography (HPLC). Of note, a subset of 11 patients received lower glucarpidase doses ranging from 10 to 31 units/kg due to a transient shortage of supply. Normalization or improvement in SCr was seen in 93% (40/43) of patients. Serum samples for immunogenicity were collected for 7 patients. Three of the 7 patients developed antiglucarpidase antibodies between 7-17 days after glucarpidase administration. Only one of the antibody-positive samples showed a slight reduction (23%) in glucarpidase activity. Detailed efficacy in the 11 patients who received the lower doses were not provided. Grade 3 and 4 toxicities, graded according to the World Health Organization (WHO), include hematological (60%), mucositis (35%), renal (19%), liver (16%), central nervous system (14%), and skin (2%).¹⁶

Heuschkel and colleagues evaluated half-dose glucarpidase at 25 units/kg in 7 adults with toxic MTX plasma concentrations. Patients ranging from 19 to 71 years of age received glucarpidase a median of 58 hours (range 42-72 hours) after the initiation of MTX. Within one day of glucarpidase administration, the MTX plasma concentrations decreased by 97.5%. The authors noted methotrexate rebound 42-73 hours after methotrexate initiation; however, the MTX concentration was consistently less than 10 μmol/L. Of the 6 patients with initial evaluable levels, five patients (83%) had MTX concentrations <1 μmol/L. All patients had levels that remained permanently <10 μmol/L. One patient received intermittent veno-venous hemodialysis because of a very high MTX level and delay in glucarpidase delivery. Significant toxicities > Grade 3 per Common Terminology Criteria for Adverse Events (CTCAE) include hepatotoxicity in 1 patient (14%), thrombocytopenia in 3 patients (43%), and leukopenia in 2 patients (29%).¹⁷

Several case reports and case series describe other methods for glucarpidase dosing. Trifilio et al. describes a case of a 59-year-old man with newly diagnosed pre-T acute lymphoblastic lymphoma starting part B of hyper-CVAD. After an increase of Scr to 2.58 mg/dL at 24 hours post-MTX and 4.54 mg/dL at 48 hours post-MTX dose, the patient became anuric. After two sessions of high-flux hemodialysis, the patient was treated with a single 1,000 unit dose of glucarpidase, which was approximately 15% of the approved dose. The MTX level 12-hours post-glucarpidase was 0.5 μmol/L. His MTX levels continued to decline and SCr improved over the next 5 days.₁₈ In a case series by Krüger et al., the authors describe 3 obese patients with elevated levels 24 hours post-MTX at 97, 52, and 19 μmol/L. Of the 3 patients, two experienced AKI. After a single dose of glucarpidase 4,000 units (approximately 50 units/kg per ideal body weight), MTX levels quickly dropped to 1.37, 0.07, and 0.03 μmol/L, respectively.19 A recent case series described 5 patients who received HDMTX infusions and had elevated 48-hour MTX levels >5 μmol/L and SCr increase >50% from baseline. The adults ranged from 38-74 years and weighed 69-156 kg. A fixed dose of 1,000 units of glucarpidase was given and all 5 patients had MTX levels undetectable within 24 hours of glucarpidase administration.²⁰ 

Alternate dosing strategies in pediatrics
Scott et al. retrospectively evaluated 26 pediatric patients ranging 4.0- 20.4 years of age who received HDMTX at St. Jude Children’s Research Hospital. Methotrexate doses were rounded to the nearest vial size and doses ranged from 13 to 90 units/kg. Patients who received glucarpidase <50 units/kg had median percent reduction in plasma concentration of 99.4% (range 90-100%) measured by HPLC compared to median percent reduction of 99.4% (range 77.2-100%) in patients who received >50 units/kg. The authors concluded there was no significant relationship between the glucarpidase dose and percent decrease in methotrexate plasma concentrations. There was also no statistically significant association found between glucarpidase dose and time to SCr recovery (P>0.8).21

Other considerations
One of the challenges in evaluating the efficacy of glucarpidase is the institution’s ability to accurately measure serum MTX levels. Within 48 hours after glucarpidase administration, immunoassays are unreliable and will overestimate the MTX level.¹³ The metabolite DAMPA cross reacts with serum MTX that is measured with the standard immunoassay. HPLC is a more sensitive method that can accurately measure serum MTX levels even during the 48-72 hour period after glucarpidase administration; however, its availability may vary across hospitals.14 One study suggests that it may take even longer than 72 hours for immunoassays to not overestimate MTX levels, thus making it challenging for providers practicing at hospitals without HPLC to know if a post-glucarpidase MTX level is accurate or possibly falsely elevated.²²

The literature describing reduced-dose glucarpidase is limited to small patient populations, thus institutions and practitioners must weigh the risk versus the benefit of administering doses lower than the FDA-approved dose. A major driving factor for using a lower dose is the high cost for each vial. Importantly, lower doses can also be justified pharmacokinetically, since glucarpidase has a mean volume of distribution of 3.6 L suggesting its distribution is restricted to plasma volume.13 Glucarpidase reduces MTX concentrations in the intravascular compartment; however, it has no impact on MTX located intracellularly or within the urinary collecting system. Thus, leucovorin rescue is still needed to address the intracellular compartment.²³ If institutions decide to routinely give a flat dose such as 2,000 units (2 vials), they may be able to justify carrying a supply on-site at all times to ensure timely administration. Some may argue that if lower doses are given initially, a second dose may be given at a later time point, if necessary. However, Widemann et al. reported that subsequent second and third doses of glucarpidase did not substantially decrease plasma MTX concentrations.⁷ Theoretically, a second dose may not be as effective in preventing MTX-induced toxicities, since by this time the majority of MTX may already be located intracellularly or converted to inactive metabolites with the first glucarpidase dose. Another limitation to subsequent doses is the potential development of antibodies to glucarpidase.

The management of toxic MTX concentrations is undoubtedly a high cost to the healthcare system. However, administration of the FDA-approved dose of glucarpidase may be the most quick and effective method proven to decrease serum MTX levels. Some may argue that perhaps it may be better to give the full dose rather than risking an inadequate decrease in MTX levels and potentially acquire other indirect costs such as increased length of intensive care unit stay or dialysis. Renal replacement therapy in the form of hemodialysis or hemoperfusion may be used to remove MTX levels from the blood. However, the decline in MTX levels is slow with frequent rebound.⁷ A retrospective study in patients admitted for HDMTX who subsequently developed MTX toxicity found that patients treated with glucarpidase had shorter average length of stay of 14.7 days compared to all nonglucarpidase patients at 21.9 days and nonglucarpidase patients who received dialysis of 40.2 days.²⁴ The study was not designed to compare length of stay among patients receiving different glucarpidase doses. It is important to also note that multiple dialysis sessions increase the risk for infection, bleeding complications, thrombocytopenia and electrolyte disturbances.

If debating whether glucarpidase is indicated in a unique patient scenario, a set of consensus guidelines offers roadmaps for decision making.¹⁴ Additionally, an open-access clinical decision-making tool is available at MTXPK.org. It uses patient-specific characteristics and pharmacokinetic modeling to compare expected vs. actual MTX elimination time curves.^25,26 If glucarpidase is needed, distributors are able to send drug to hospitals through expedited or next day delivery.²⁷ Administration of drug is time-sensitive, as early administration <96 hours after HDMTX exposure has been shown to decrease MTX-related toxicities. Grade 4 toxicity developed in 9/64 (14%) patients who received glucarpidase <96 hours compared to 6/11 (55%) of patients >96 hours.²⁸ The availability of drug and treatment timeline should be considered when evaluating whether to keep drug on-hand. Currently, practices vary by hospital. For example, the Mayo Clinic implemented an institutional protocol to administer fixed-dose glucarpidase at 1,000 units/dose and to carry 2 vials on-site after evaluating successful results in their case series.²⁰ The consensus guidelines for stocking antidotes recommend routinely stocking 5 vials.²⁹

Conclusion
Because glucarpidase is an antidote, its rare indication and limited number of patients in studies makes it challenging to determine the most effective, safe, and economical dosing strategy. It is the responsibility of each institution that administers HDMTX to assess its need to add glucarpidase to formulary and determine how to routinely stock or procure the medication. 

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