Case files of the New York City Poison Control Center: Antidotal strategies for the management of methotrexate toxicity

Silas W. Smith MD 0 1 Lewis S. Nelson MD 0 1 0 New York University School of Medicine , New York, NY 1 New York City Poison Control Center , New York, NY - CASE PRESENTATION A 10-year-old boy (37.5 kg; body surface area 1.26 m2) with osteosarcoma of the right humerus received a planned 4-hour infusion of high-dose methotrexate (16 g, 12.7 g/m2). His previous medical history was notable for an implanted central venous catheter placement complicated by Horners syndrome. Renal and hepatic functions were normal at baseline. A postinfusion methotrexate concentration was uninterpretable, but the significance of this result was not initially appreciated by the treating clinicians. Over the next 48 hours, the child developed blurry vision, painful mucositis, stomatitis, and facial blistering. Reported vital signs were: BP, 121/82 mm Hg; pulse, 111/minute; respirations, 16/minute. A physical examination was consistent with the reported symptoms. The 48-hour postinfusion serum methotrexate concentration at the time of poison control center (PCC) consultation was 171 mol/L (Figure 1). Methotrexate (MTX) is a folate analogue antimetabolite commonly used in treating blood and solid organ malignancies, dermatological and rheumatic diseases, and in termination of gestation. When first introduced as chemotherapeutic agents, folic acid conjugates produced an accelerated progression in the bone marrow and viscera of children with acute leukemia, suggesting treatment options with folate antagonists. Subsequently, the antifolate aminopterin (4-aminopteroyl-glutamic acid) produced the first reported clinical success in inducing temporary remission in acute leukemia in 1948 [1]. Aminopterins significant toxic side effects spurred a search for alternative antifolate agents with a broader therapeutic window, and led to aminopterins substitution by MTX (amethopterin) [24]. MTX later provided the first medical cure of a solid cancer [5]. The FDA approved MTX for use in psoriasis in 1971, and it found additional use in the treatment of dermatomyositis, pemphigus and pemphigoid, and pityriasis rubra pilaris [6]. One of several disease-modifying antirheumatic drugs (DMARDs), MTX received an FDA indication for use in adults with severe, active rheumatoid arthritis in 1988 with extension to children with active polyarticular-course juvenile rheumatoid arthritis [7]. A 1982 report first described the use of MTX in the treatment of interstitial ectopic pregnancy [8]. Since then, MTX has become an accepted abortive medical therapy for ectopic gestations [9]. MTX is also used off-label in combination with misoprostol for elective medical termination of pregnancy [10]. MTX provides prophylaxis against graft-versus-host disease, particularly in allogeneic stem cell transplantation with peripheral-blood stem cells or bone marrow [11,12]. How is methotrexate dosed? Methotrexate may be administered via intramuscular (IM), intrathecal (IT), intravenous (IV), or oral (PO) routes. Dosing is quite diverse due to the significant variations in MTX indication. High-dose methotrexate (HDMTX) for chemotherapy, which requires leucovorin rescue, is MTX, 1 g/m2 IV [13]. Lower doses may be used in alternative chemotherapeutic regimens, while up to 812 g/m2 or more may be given for osteosarcoma, leukemia, and lymphoma [1416]. IT MTX is more appropriately dosed by age, as a fixed dose per m2 was reported to result in low Figure 1: Methotrexate infusion (solid line), serum MTX concentrations by immunoassay (circles), and high-dose leucovorin (1500 mg/m2) and CPDG2 administration (arrows). cerebrospinal fluid (CSF) methotrexate concentrations and reduced efficacy in children, and in high concentrations and neurotoxicity in adults [17,18]. Psoriasis patients are normally provided MTX 7.530 mg PO weekly [19]. Rheumatoid arthritis treatment similarly involves MTX 7.520 mg PO weekly [20]. Multiple fatalities and serious adverse events have resulted from prescription, dispensing, administration, and patient errors in which the intended weekly dose was incorrectly consumed daily [21,22]. For termination of ectopic pregnancy, MTX 50 mg/m2 IM is commonly used [9]. In elective termination of pregnancy, MTX 2575 mg/m2 IM or 2550 mg PO in combination with misoprostol are employed [10]. How is methotrexate metabolized? Intracellularly, folypolyglutamyl synthase adds gamma-linked glutamate groups to MTX [23]. Polyglutamation increases the intracellular half-life of MTX, allowing it to persist despite extracellular MTX elimination or removal [24]. MTX can also be hydroxylated at the 7-position by hepatocyte aldehyde oxidase to yield 7-OH-MTX [14]. In the gut, bacterial carboxypeptidase converts MTX to 4-amino-4-deoxy-10-methylpteroic acid (DAMPA) [24]. What are the pharmacokinetics of methotrexate? Methotrexate is a weak acid with a pKa of 4.85.5, thus is ionized at physiological pH [14]. About 50% protein binding occurs, regardless of serum concentration [25]. Route o (...truncated)