Use of glucarpidase in high-dose methotrexate-induced nephrotoxicity

High-dose methotrexate (HD-MTX) is an important component in the treatment of a variety of childhood and adult cancers. Although HD-MTX is safely administered to most patients, it may lead to significant toxicity. Many factors could be involved in the toxic effect of HD-MTX: a) drug-drug interactions. More specifically, NSAIDs, penicillins, fluoroquinolones and proton pump inhibitors increase MTX exposure in tissues mainly by reducing tubular secretion; b) renal dysfunction; c) decreased gastrointestinal (GI) motility, which can increase the enterohepatic circulation of MTX; d) pleural and peritoneal effusions, which are third-space fluids and serve as reservoirs. Although MTX diffuses easily into these loculations, it is eliminated with difficulty because of poor vascularity. Thus, as MTX slowly distributes back into plasma via passive diffusion, the duration of exposure may be greatly increased. The primary dose-related toxicities of HD-MTX are mucositis and bone marrow suppression, because of cytotoxicity at relatively low plasma levels: an MTX serum level of 5 and 10 μmol/L is the threshold for inhibition of DNA synthesis in both the GI mucosa and bone marrow, respectively. Kidney toxicity is due to poor MTX solubility in acidic fluids, like urine. The drug’s solubility threshold in the kidney increases from 1 mg/mL when urine pH is 5.7 to 10 mg/mL with a pH of 6.9. The aqueous solubility of 7-OH-MTX, its main metabolite, is 3–5-fold less than that of MTX; as a result, during high-dose infusions, MTX and 7-OH-MTX may precipitate in the kidney if adequate hydration and urinary alkalinization are not maintained. Their precipitation in the renal tubules and collecting ducts produces obstructive nephropathy, which is the most common cause of MTX-induced nephrotoxicity. MTX is also reported to cause interstitial nephritis. In patients with normal kidney function, HD-MTX is safe if administered with hyper-hydration, urine alkalization, and pharmacokinetically guided leucovorin rescue therapy. Prompt recognition of delayed methotrexate elimination (DME) and renal dysfunction are required for the successful management of methotrexate toxicity, even though an increase in serum creatinine levels or a decrease in urine production represent a medical emergency. Increased hydration, high-dose leucovorin, and glucarpidase rapidly and effectively reduce serum methotrexate concentrations, protecting cells from high exposure. If administered as soon as toxicity is detected, they can prevent further damage, aid renal recovery, and allow HD-MTX therapy to be completely resumed after renal function is restored. Despite the adoption of the best supportive care (BSC) (leucovorin rescue, hydration and alkalinization), up to 1.8% of children and 6.4% of adults treated with HD-MTX will develop DME and acute kidney injury (AKI). Beyond mechanical methods, the only drug able to enzymatically clear most of the MTX from the serum in a very short time is glucarpidase, which is highly effective against HD-MTX-induced toxicity. Glucarpidase is a recombinant bacterial enzyme composed of 390 amino acids with a molecular weight of 83 kDa and that rapidly hydrolyzes circulating MTX into 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate, mainly eliminated by the liver. Interestingly, within 15 minutes of administration, glucarpidase quickly and predictably metabolizes only circulating MTX, reducing its concentration by more than 95%. By providing an alternative route for MTX elimination, glucarpidase is very effective for patients at risk of MTX toxicity secondary to DME. The pharmacokinetics of glucarpidase is characterized by a small distribution volume of 3.55 L, which demonstrates that the enzyme is distributed in plasma but not in tissues, owing to its large molecular size. Glucarpidase does not cross the cell membrane or the blood-brain barrier and thus does not interfere with the anticancer efficacy of MTX in the cell or in the CNS. Similarly, the drug does not cross the renal glomeruli and no activity is recovered in the urine. At therapeutic doses, glucarpidase reaches maximum plasma levels (Cmax) of 3.3 μg/mL and, after 5 half-lives (approximately 45 hours), it is completely eliminated from the body. It is metabolized by the liver into amino acids with a low mean systemic clearance (Cl) of 7.5 mL/min and a relatively short half life (t1/2): if we consider enzyme activity, t1/2 is 5.6 hours, while the t1/2 calculated on serum levels is approximately 9 hours. No dose adjustment is required in patients with renal impairment or in the pediatric population. If we compare glucarpidase and leucovorin rescue, it should be noted that leucovorin provides intracellular rescue (allowing resumption of DNA and RNA synthesis) and it is not a competitor of glucarpidase, which does not cross the cytoplasmic membrane. Leucovorin does not clear MTX from the body nor does it break the vicious circle of DME, MTX precipitation and nephrotoxicity. Leucovorin competes with MTX for transport into the cell; it is less effective as a rescue agent at high MTX concentrations and, at very high-doses (over-rescue), it may lead to treatment failure, impacting MTX efficacy at the next HD-MTX course. Current methods for removing MTX, including extracorporeal methods, are suboptimal, as they are slow and potentially associated with a higher risk of infection and hemorrhage in patients affected by neutropenia and thrombocytopenia. Glucarpidase is associated with a fast, clinically relevant (99% or greater) and sustained reduction of serum MTX levels, providing noninvasive rescue from MTX toxicity, also in renally impaired patients.