What are the typical dosing ranges for methotrexate (MTX) in the treatment of various conditions, including rheumatoid arthritis, psoriasis, and cancer, considering factors such as patient's overall health status and impaired renal function?

Methotrexate Dosing: Low vs High Dose Ranges Across Conditions

Methotrexate dosing is fundamentally divided into low-dose therapy (7.5-25 mg weekly) for inflammatory conditions like rheumatoid arthritis and psoriasis, versus high-dose therapy (≥500 mg/m² per course) for malignancies, with these two regimens having entirely different pharmacologic profiles, toxicity patterns, and monitoring requirements. 1, 2

Low-Dose Methotrexate (Inflammatory Conditions)

Rheumatoid Arthritis Dosing

• Start at 7.5-15 mg orally once weekly, with rapid escalation to at least 15 mg weekly within 4-6 weeks to optimize efficacy. 3, 1
• The dose may be adjusted gradually by 5 mg every 2-4 weeks until achieving adequate disease control or reaching the maximum tolerated dose, with a target range of 20-25 mg weekly for optimal efficacy. 3
• Doses exceeding 20 mg/week significantly increase the incidence and severity of serious toxic reactions, especially bone marrow suppression. 1
• The plateau of efficacy is attained at approximately 10 mg/m²/week in most patients, though individual variability exists. 4
• Alternative dosing: 2.5 mg at 12-hour intervals for 3 doses given as a course once weekly. 1

Psoriasis Dosing

• Typical dosing ranges from 7.5 mg to 25 mg weekly, administered as a single dose or divided into 3 doses over 24 hours. 5
• Start with either a test dose of 2.5-5 mg (followed by CBC 5-7 days later) or begin directly at a therapeutic dose such as 15 mg weekly. 5
• In direct comparison, 25 mg weekly dosing acts faster than 10 mg weekly but causes more severe adverse effects. 5
• Dosages of 30 mg/week should not ordinarily be exceeded. 1
• Daily dosing (2.5 mg daily for 6 days/week) shows less benefit than weekly dosing and causes more liver enzyme elevation. 5

Juvenile Rheumatoid Arthritis

• The recommended starting dose is 10 mg/m² given once weekly. 1
• Children receiving 20-30 mg/m²/week (0.65-1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects with intramuscular or subcutaneous administration. 1

High-Dose Methotrexate (Malignancies)

Definition and Dosing Range

• High-dose methotrexate is defined as doses of 500 mg/m² or greater, used for malignant disorders including leukemia and cancers of the lung, breast, and uterus. 2
• The 1 gram vial should be reconstituted with 19.4 mL to a concentration of 50 mg/mL for IV infusion. 1

Critical Prerequisites for High-Dose Administration

• Serum creatinine must be normal and creatinine clearance must be greater than 60 mL/min before initiation. 1
• If serum creatinine increases by 50% or more compared to prior value, creatinine clearance must be documented to be >60 mL/min even if creatinine remains in normal range. 1
• Patients must be well hydrated with 1,000 mL/m² IV fluid over 6 hours prior to methotrexate infusion. 1
• Continue hydration at 125 mL/m²/hr (3 liters/m²/day) during infusion and for 2 days after completion. 1
• Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin therapy using sodium bicarbonate. 1

Mandatory Monitoring for High-Dose Therapy

• Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until methotrexate level falls below 5 x 10⁻⁸ mol/L (0.05 micromolar). 1
• Leucovorin rescue dosing is based on serum methotrexate levels, with standard rescue dose of 15 mg IV or orally every 6 hours. 6, 1

Route of Administration Considerations

Oral vs Parenteral for Low-Dose Therapy

• Oral administration is preferred initially due to ease of administration and similar bioavailability at typical starting doses. 3
• Switch to subcutaneous administration at the same dose if inadequate response at 15-20 mg oral weekly or if gastrointestinal intolerance develops, before further dose escalation. 3
• Intramuscular and subcutaneous injections result in comparable pharmacokinetics and are interchangeable. 4
• Oral methotrexate exhibits marked interindividual variability in absorption extent, though intraindividual variability is moderate. 4

Dosing Adjustments for Renal Impairment

Low-Dose Therapy Adjustments

• For GFR >90 mL/min: Use normal dose. 3
• For GFR 20-50 mL/min: Reduce dose by 50%. 3
• For GFR <20 mL/min: Avoid methotrexate entirely. 3
• In rheumatoid arthritis, methotrexate is contraindicated if eGFR is <30 mL/min. 2
• A lower initial dose should be considered with eGFR between 30-59 mL/min, with more gradual dosage increase and lower weekly maximum. 2

High-Dose Therapy Requirements

• Adequate renal function must be documented with creatinine clearance >60 mL/min before each course. 1
• Methotrexate is mainly excreted by the kidney as intact drug through glomerular filtration, tubular secretion, and reabsorption. 4

Mandatory Folate Supplementation

Standard Supplementation Protocol

• All patients on methotrexate must receive folic acid supplementation: 5 mg weekly (on a different day than methotrexate) or 1 mg daily except on methotrexate day. 3, 7
• Folic acid supplementation reduces GI side effects by 58% and hepatotoxicity by 83% without compromising therapeutic efficacy. 7
• Never administer folic acid on the same day as methotrexate, as it may compete for cellular uptake and reduce therapeutic efficacy. 7
• For patients on methotrexate ≥12.5 mg weekly, prescribe at least 5 mg folic acid weekly. 3

Escalation for Intolerance

• If intolerable side effects persist despite standard supplementation, increase folic acid to 5 mg daily before reducing methotrexate dose. 7
• Consider increasing to 7-10 mg folic acid weekly for patients on methotrexate >15 mg/week. 7

Folic Acid vs Folinic Acid

• Use folic acid (not folinic acid) for routine supplementation due to lower cost and similar effectiveness. 7
• Reserve folinic acid (leucovorin) exclusively for methotrexate overdose or severe toxicity as rescue therapy. 7, 6

Monitoring Requirements by Dose Range

Low-Dose Therapy Monitoring

• First 3 months: CBC, liver function tests, and creatinine at least monthly. 6
• After stabilization: CBC and liver function tests every 3-6 months. 6
• During dose escalation: CBC, liver function tests, and creatinine every 1-1.5 months. 3
• Wait 4 weeks after each dose increase before assessing response, as clinical improvement takes this long to manifest. 3

High-Dose Therapy Monitoring

• Serum methotrexate level monitoring is mandatory, measured 24 hours after starting and at least daily until <0.05 micromolar. 1
• Patients with delayed methotrexate elimination are likely to develop nonreversible oliguric renal failure and require continuing hydration, urinary alkalinization, and close fluid/electrolyte monitoring. 1

Efficacy Timeline and Duration

Response Expectations

• Therapeutic response to low-dose methotrexate usually begins within 3-6 weeks, with continued improvement for another 12 weeks or more. 1
• Dosage changes frequently take at least a month for clinical response in psoriasis. 5
• Initial clinical improvement is maintained for at least two years with continued therapy in rheumatoid arthritis. 1
• When methotrexate is discontinued, arthritis usually worsens within 3-6 weeks. 1

Critical Pitfalls to Avoid

Dosing Errors

• Do not escalate doses more frequently than every 2 weeks, as insufficient time will have elapsed to assess therapeutic response or identify delayed toxicities. 3
• Do not exceed 20 mg weekly in patients with risk factors for toxicity (advanced age, renal impairment, significant alcohol use). 3
• Do not continue escalating if adequate disease control is achieved at lower doses—use the minimum effective dose to minimize cumulative toxicity. 3

High-Dose Therapy Errors

• Do not administer leucovorin intrathecally—this is contraindicated. 1
• Do not delay leucovorin administration, as efficacy diminishes dramatically after 24 hours. 6
• Do not confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block for acute toxicity. 6

Drug Interactions

• Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk. 6
• NSAIDs reduce renal elimination of methotrexate, which is particularly dangerous with any dose. 6