Why is methotrexate (MTX) given on a weekly basis?

Why Methotrexate is Administered on a Weekly Basis

Methotrexate is administered on a weekly basis because this dosing schedule maximizes therapeutic efficacy while minimizing toxicity, as weekly dosing aligns with the cell cycle kinetics of target tissues and reduces serious adverse effects that would occur with more frequent administration. 1

Pharmacological Rationale

Cell Cycle Considerations

• Methotrexate works by inhibiting dihydrofolate reductase, which decreases folate cofactors required for DNA synthesis and cellular replication 2
• The weekly dosing schedule was originally developed based on the understanding of psoriatic keratinocyte cell cycle kinetics, which have a turnover time of approximately 7 days 1
• The rationale for weekly dosing is to interfere with the prolonged S phase of the cell cycle in proliferating cells 1

Immunomodulatory Effects

• At low doses (<25 mg per week), methotrexate primarily decreases proliferation of lymphoid cells, providing an immunosuppressive effect that is the main mechanism of action in psoriasis and rheumatoid arthritis 1
• The active polyglutamate metabolites of methotrexate have a half-life of approximately 3 days, providing sustained therapeutic effects throughout the week 1

Clinical Evidence Supporting Weekly Dosing

Comparative Efficacy Studies

• Direct comparison studies have shown that weekly dosing is superior to daily dosing (2.5 mg daily for 6 days of the week) in terms of efficacy 1
• A pilot double-blind controlled study comparing twice-weekly versus once-weekly methotrexate in rheumatoid arthritis found no advantage to the twice-weekly regimen, confirming that once-weekly dosing is optimal 3

Safety Considerations

• Daily dosing has been associated with higher rates of liver enzyme elevations compared to weekly dosing 1
• Weekly dosing significantly reduces the risk of severe toxicity, particularly bone marrow suppression and hepatotoxicity 1
• Serious and potentially fatal toxicity can occur when methotrexate is mistakenly taken daily instead of weekly 4

Dosing Recommendations

Standard Dosing

• For psoriasis and rheumatoid arthritis, methotrexate is typically administered in doses ranging from 7.5 mg to 25 mg once weekly 1
• The dose can be given as a single dose or divided into three doses over a 24-hour period (for patients who experience significant gastrointestinal side effects) 1
• Doses should be adjusted to the individual patient to obtain adequate disease control while minimizing side effects 1

Administration Routes

• Methotrexate can be administered orally, subcutaneously, or intramuscularly on a weekly basis 1, 5
• Subcutaneous administration provides more consistent bioavailability than oral dosing and may be preferred for patients with inadequate response to oral therapy 4

Toxicity Reduction Strategies

Folate Supplementation

• Concomitant folic acid supplementation (1-5 mg daily except on methotrexate day) is recommended to reduce the frequency of adverse effects 1, 4
• Folate supplementation has been shown to decrease hepatic laboratory abnormalities and gastrointestinal side effects without compromising efficacy 1, 6

Monitoring

• Regular monitoring is essential with weekly methotrexate therapy:
  • Complete blood count (CBC) every 2-3 months once therapy is stabilized
  • Liver function tests every 4 weeks initially, then every 2-3 months
  • Renal function tests every 2-3 months 1, 4

Common Pitfalls and Warnings

Dosing Errors

• The most dangerous pitfall is incorrect daily administration instead of weekly dosing, which can lead to fatal toxicity 4
• Patients should be clearly instructed that methotrexate is taken ONCE WEEKLY, not daily 4
• Healthcare providers should emphasize the importance of taking methotrexate on the same day each week 4

Risk Factors for Toxicity

• Risk factors for methotrexate toxicity include:
  • Advanced age
  • Renal impairment
  • Lack of folate supplementation
  • Drug interactions (particularly with NSAIDs, certain antibiotics, and alcohol)
  • Hypoalbuminemia 1

In conclusion, the weekly dosing schedule of methotrexate represents a carefully balanced approach that provides optimal therapeutic benefit while minimizing potentially serious toxicity. This dosing strategy has been validated through decades of clinical experience and research, making it the standard of care for methotrexate administration in inflammatory conditions.