Methotrexate: is acute oral overdose ever a concern?

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1 Methotrexate: is acute oral overdose ever a concern? Dr Betty Chan Emergency Physician & Clinical Toxicologist Prince of Wales Hospital New South Wales Poisons Information Centre

2 Case Study 1 53F(80kg) Methotrexate (MTX) 10mg x 65 = 650mg + ETOH Ingestion 3 hrs ago She takes 10mg MTX weekly for psoriatic arthritis. Last dose was 1 week ago and takes folate on other days. Nil GI symptoms, normal renal function. Patient is otherwise well. What is your risk assessment & how would you manage this patient?

3 Questions Would this patient develop toxicities such as gastrointestinal or myelosuppression from acute MTX ingestion? Would you monitor the serum methotrexate concentration? How would you treat this patient? Would you treat this patient with IV or oral folinic acid?

4 Objectives Discuss the pharmacokinetic & mechanism of action of MTX. Analyse therapeutic & oncology studies that provide pharmacokinetic or clinical data on MTX toxicities. Present New South Wales Poisons Information Centre data & other series on acute MTX poisoning. Outline the management of acute MTX poisoning.

5 Introduction Methotrexate (MTX) is a folic acid antagonist, First developed in the 1950s. Originally used as chemotherapeutic agent. Later used in low doses to treat autoimmune disease and for the nonsurgical management of ectopic pregnancy. Limited clinical data on acute oral poisoning, but there are oncology and rheumatology clinical data in methotrexate toxicities.

6 Pharmacokinetics of Methotrexate Methotrexate is lipophilic, 50% protein bound & has a small volume of distribution 0.7 L/kg. Primarily excreted by the kidneys. Urine MTX solubility is directly proportional to ph, it precipitates in acidic urine (ph<5.5) & solubility 10 fold greater at ph 7. Distribution half-life is about 2 hours while the elimination half-life varies from 6 to 8 hours. Serum MTX concentration becomes undetectable by 24 hrs post ingestion.

7 Pharmacokinetics of methotrexate Oral bioavailability of MTX appears to be saturable. The absorption is dependent on an active transporter (folate carrier-1 protein). MTX competes with folinic acid for the active transporter. Bioavailability is about 70% in low dose ingestion.

8 Bioavailable dose versus ingested dose in adults and children 40 Bioavailable dose (mg/m 2 ) Adults C hildren Bioavailable dose mg/m Dose (mg/m 2 )

9 Bioavailability of Methotrexate 40 In single acute ingestion, there is a likely maximal bioavailable dose of 14.4 ±1.6 mg/m 2. Staggered MTX administration to a total dose of 200 mg/m 2 given to patients over a 4 hour period showed a bioavailability of 28% +/- 4%. Bioavailable dose (mg/m 2 ) Adults C hildren Bioavailable dose mg/m Dose (mg/m 2 )

10 Mechanism of methotrexate toxicity MTX entered the cells and are metabolised to polyglutamate derivatives that have a median halflife of 1-4 weeks. The polyglutamate derivatives cause cytotoxicity through inhibition of dihydrofolate reductase. MTX prevents DNA and RNA synthesis by inhibiting the enzyme dihydrofolate reductase. Folinic acid is a methotrexate antagonist and an active form of folate that bypasses di-hydrofolate reductase.

11 Oncology Data High dose MTX used in oncology varies from 1-33 g/m 2 given either as a single or combination therapy. With a high dose of 9 g/m 2, the peak plasma concentration is about 10-2 to 10-4 mol/l. Moderate dose 690 mg/m 2 infused over 42 h with delayed folinic acid rescue, plasma conc is just under 10 umol/l. Bleyer WA - Cancer, 1978;41:36-51.

12 Acute Methotrexate Toxicity 1. Critical minimal extracellular MTX concentration. 2. Duration of exposure. 3. The severity of toxicity is directly proportional to the duration of exposure and less on MTX concentration. For example, a MTX infusion which produced a peak plasma MTX conc 500 µmol/l showed no severe myelosuppression if folinic acid was commenced within 36 h. Myelosuppression was observed with prolonged MTX infusion > 36 hr irrespective of the total dose used & treatment with folinic acid at the end of the infusion. Goldie JH et al. Europ J Cancer 1972;8(4):

13 The longest infusion produced the greatest toxicity

Toxic Dose of Methotrexate In cancer patients, no rescue treatment with folinic acid if MTX IV dose <1 g/m 2 in patients with normal renal function.

14 Toxic Dose of Methotrexate In cancer patients, no rescue treatment with folinic acid if MTX IV dose <1 g/m 2 in patients with normal renal function. No folinic acid is recommended if plasma MTX conc is below the treatment line. For a small size adult, 1 g/m 2 is equivalent to an IVI MTX dose of 1300 mg (assuming the BSA is > 1.3 m 2 ). Bleyer WA - Cancer, 1978;41:36-51.

15 New South Wales Poisons Information Centre audit: cases of acute oral MTX poisoning 15 paediatric ingestion Median age of 2 (IQR: 2-2; range: 1-4). Median reported paediatric ingestion was 50mg (IQR:10-100) 36 patients with deliberate acute MTX poisoning, Median age was 47 years (IQR:31 62; range:10-85) Median dose of 325mg (IQR:85 500, range: ). 19 patients had serum MTX concentration measured, none were above the nomogram. No patient reported adverse sequelae.

16 NSW PIC from Serum MTX concentrations of patients with acute poisoning & the chemotherapy folinic acid rescue nomogram line. The equation for the extrapolated toxicity line is y=-0.042*x+2. Level (µ mol/l) Acute MTX conc (µ mol/l) Folinic rescue nomogram line (µ mol/l) Toxicity line Extrapolated toxicity line Tim e (h)

17 Study Study Design No. patients Dose Symptoms of Toxicity Wieferich K et al. Clin tox. 2014;52: Retrospective study of PIC 25 Range: mg No toxicity Bebarta V.S et al. J toxicology Retrospective study of 6 PIC ( ) mg (range mg) DSP: 47.5 mg ( mg) Abdominal pain, mucositis, nausea, dizziness or headache. LoVecchio F et al. J med tox 2008;4: Thornton S.L et al. Clinical toxicology. 2011;49:551 Retrospective study of PIC ( ) Retrospective paediatric study of PIC ( ) Accidental antineoplastic ingestion. 13 Average: 13 mg Nil 76 None significant.

18 Methotrexate toxicity Toxicity is dependent primarily on duration of exposure rather than concentration and patient s renal function. Potentially toxic to multiple organs including bone marrow, liver, gastrointestinal tract, renal, respiratory, dermatological and haematological systems, Resulting in severe myelosuppression, nausea, vomiting, stomatitis, mucositis, hepatoxicity and renal failure. Symptoms caused by bone marrow suppression usually occur at about 1 week but resolve at about 2 weeks after exposure. Renal failure is thought to be caused by the formation of intrarenal MTX crystals. Renal damage reduces MTX clearance, resulting in persistent elevation of MTX concentration and this causes further MTX crystal formation and renal injury.

19 Approach to acute MTX Poisoning In general no treatment is required for acute MTX ingestion. Oral folinic acid may be used in large and/or staggered ingestion. There is no need to monitor MTX concentration. The only exception is if patient has renal impairment as it will delay renal excretion and prolong duration of exposure.

20 Management of acute MTX overdose with renal impairment. Decontamination with AC is unlikely to be useful due to its saturable bioavailability. Could consider giving oral folinic acid to compete with absorption of MTX. Alkaline diuresis to prevent exacerbation of renal failure. Antidote: IV Folinic acid as a methotrexate antagonist.

21 Case Study 1 Progress 53F(80kg) Methotrexate 10mg x 65 = 650mg + ETOH Withheld MTX for 2 weeks. Follow up: normal WCC 2 week post MTX ingestion. Well otherwise.

22 Conclusion In acute accidental or deliberate MTX poisoning, no toxicity is expected due to its saturable bioavailability (except for renal impairment). There is no rationale to monitor MTX concentration in acute poisoning. Oral folinic acid may be used to compete with absorption in large and/or staggererd ingestions. Intravenous folinic acid may be used as a competitive methotrexate antagonist in patients with renal impairment.

23 Acknowledgement The authors would like to thank the staff (especially Dr Murray & Balit) at the NSW Poisons Information Centre for identifying and recruiting patients with acute methotrexate poisonings.

Calcium folinate as equivalent to folinic acid 50 mg/5 ml, 100 mg/10 ml COO - Ca2+, xh2o CH 2

Product Information LEUCOVORIN CALCIUM INJECTION Calcium folinate as equivalent to folinic acid 50 mg/5 ml, 100 mg/10 ml NAME OF THE MEDICINE Non-proprietary name: calcium folinate Chemical name: calcium