Mycophenolate mofetil
Mycophenolate mofetil
Generic Name
Mycophenolate mofetil
Mechanism
- Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA).
- MPA selectively and reversibly inhibits inosine monophosphate dehydrogenase (IMPDH), the rate‑limiting enzyme in the de novo purine synthesis pathway.
- By depleting guanosine nucleotides, it preferentially suppresses the proliferation of T‑ and B‑lymphocytes (which rely heavily on de novo synthesis) while sparing non‑proliferating cells.
- Secondary effects include inhibition of interleukin‑2 (IL‑2) receptor expression and reduced cytokine production, further dampening alloimmune responses.
Pharmacokinetics
| Parameter | Approximate Value |
| Absorption | Oral bioavailability ~40%; rapidly converted to MPA after first‑pass metabolism. |
| Distribution | Highly protein‑bound (~95%); crosses placenta and lactation. |
| Half‑life | 17–20 h for MPA; dose‑dependent due to saturable metabolism. |
| Metabolism | Hepatic glucuronidation (UGT1A9) to MPAG; enterohepatic recirculation contributes to prolonged exposure. |
| Excretion | Primarily renal (≈75% as MPAG); reduced clearance in renal impairment requires dose adjustment. |
| Drug interactions | Cimetidine, valproic acid, antacids can increase MPA exposure; cyclosporine may affect bioavailability. |
Indications
- Solid organ transplantation (kidney, liver, heart, lung): maintenance immunosuppression.
- Autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus (when steroid‑sparing).
- Cutaneous disorders: severe psoriasis, pemphigus vulgaris.
- Inflammatory bowel disease: refractory ulcerative colitis or Crohn’s disease in combination with other agents.
- Other: occasionally used off‑label for idiopathic pulmonary fibrosis and certain transplant rejection episodes.
Contraindications
- Absolute contraindications: hypersensitivity to mycophenolate or its excipients.
- Relative contraindications:
- Active infections (especially viral, bacterial, fungal).
- Pregnancy (category D; teratogenic potential).
- Significant myelosuppression or cytopenias.
- Severe renal or hepatic impairment (dose adjustment or avoidance).
- Warnings:
- Infections: ↑ risk of opportunistic infections (e.g., CMV, PCP).
- Neoplasia: increased long‑term risk of malignancies, particularly lymphomas.
- Gastrointestinal toxicity: diarrhea, nausea, abdominal pain.
- Bone marrow suppression: anemia, neutropenia, thrombocytopenia.
Dosing
| Patient | Starting Dose | Maintenance Dose | Administration Notes |
| Kidney transplant (adult) | 1 g PO BID | 1 g PO BID (or 500 mg BID if concomitant tacrolimus) | May reduce dose in early post‑transplant period for infection control. |
| Liver transplant (adult) | 500 mg PO BID | 600–800 mg PO BID | Titrate per drug levels and rejection risk. |
| Autoimmune disease | 1 g PO BID | 1–1.5 g PO BID | Initiate with tapered steroid regimen. |
| Infants (renal transplant) | 10 mg/kg PO BID | 20 mg/kg PO BID | Monitor drug levels due to variable PK. |
• Take on an empty stomach to improve absorption; if GI intolerance, split dose with meals.
• For renal impairment, reduce maintenance dose by 25–50 % (e.g., 500 mg BID).
• For hepatic impairment, monitor closely; avoid if severe dysfunction.
Monitoring
- Baseline: CBC, CMP, renal & hepatic panels, viral serology (HBV, HCV, EBV, CMV), pregnancy test.
- Periodic:
- CBC & CMP every 1–2 weeks for 3 months, then monthly.
- MPA trough levels (if available) every 2–4 weeks during dose titration.
- Renal function annually (or more frequently if reduced dose).
- Screening for infections (urinalysis, chest X‑ray) at baseline, 6 months, and yearly.
- Tumor markers & imaging (as per transplant protocol) for malignancy risk.
Clinical Pearls
- Enterohepatic recycling: fasting or delayed meals can prolong MPA exposure; advise consistent timing.
- Interaction with cyclosporine: concurrent therapy may reduce mycophenolate bioavailability; consider higher dose or monitor levels.
- Dose adjustment in pregnancy: avoid; if inadvertent exposure occurs, consider switching to azathioprine.
- Antiviral prophylaxis: combine with valganciclovir for CMV risk in transplant patients; prophylactically treat PCP with TMP‑SMX if neutropenia.
- Diarrhea management: first‑line: increase fluid intake and electrolytes; if refractory, consider dose reduction or temporary hold on MPA while maintaining immunosuppressive coverage.
- Hematologic monitoring: a 25% drop in ANC or platelets warrants dose reduction or temporary discontinuation.
- Bone marrow suppression risk is dose‑related: use the minimum effective dose, especially when combining with other myelosuppressants.
*References available upon request.*