Mycophenolate

Mycophenolate Mofetil & Mycophenolate Sodium

  • – Mycophenolate Mofetil: prodrug of Mycophenolic acid (active metabolite), with greater bioavailability & tolerability than Mycophenolic acid
  • – Pregnancy Category D

Availability

  • Oral Mycophenolate Mofetil (250 mg & 500 mg)
  • Oral enteric coated MPS “Myfortic” (360 mg & 720 mg)
  • Intravenous 

Oral dose

  • Adults:1-3 grams/day divided into 2 doses 
  • Pediatrics:30-50 mg/kg/day in atopic dermatitis 

Note

  • Start with 500 mg at bedtime for 1 week then increase to 500 mg twice daily then increase by 500 mg increment every 2- 4 weeks
  • Studies indicated Mycophenolate Mofetil & enteric coated MPS have similar efficacy (1 gram twice daily of Mycophenolate Mofetil = 720 mg of MPS twice daily)

  • Inhibits de-novo purine synthesis by selectively & non-competitively inhibiting inosine monophosphate dehydrogenase (IMPDH) leading to blocking of synthesis of guanine nucleotide & subsequent incorporation into DNA (T & B lymphocytes lack purine salvage pathway so DNA synthesis is preferentially inhibited in those cells). Depriving T & B lymphocytes of purine metabolites leading to decreased growth & replication with a net result of selective immunosuppression
  • Decreased antibody formation by B lymphocytes
  • Decreased recruitment via downregulating expression of vascular cell adhesion molecule (VCAM), E-selectin and P-selectin
  • Decreased delayed type hypersensitivity reaction by inhibiting proliferative responses to mitogenic stimulation 
  • Inhibits fibroblasts: explaining Mycophenolate Mofetil implication in fibrosing diseases

  • Nearly 100% bioavailable 
  • Mycophenolate Mofetil rapidly absorbed then converted by esterases in plasma, liver, & kidneys to active metabolite Mycophenolic acid. Mycophenolic acid then inactivated in liver via glucuronidation to mycophenolic acid glucuronide (MPAG), then excreted into the gastrointestinal tract via bile acid secretion. Mycophenolic acid glucuronide (MPAG) remains inactive until it is converted back to Mycophenolic acid by the enzyme β-glucuronidase which is then reabsorbed. This enterohepatic recirculation is vital for maintaining mycophenolic acid/ mycophenolic acid glucuronide serum levels. 

Note: High levels of β-glucuronidase found in skin & gastrointestinal tract explaining therapeutic efficacy of Mycophenolate Mofetil in Dermatology & Mycophenolate Mofetil ’s most common side effect (Gastrointestinal)

  • 2 plasma peaks: 1 hour after dosing & 6-12 hours after enterohepatic circulation 
  • ½ life ~16 hours
  • 90% excreted in urine as mycophenolic acid glucuronide

FDA

  • Renal, cardiac, & liver organ transplant 

Off label

  • Dermatitis: psoriasis, Atopic dermatitis, chronic actinic dermatitis 
  • Bullous dermatoses: bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceous, paraneoplastic pemphigus, linear IgA bullous dermatosis, mucous membrane pemphigus, epidermolysis bullosa acquisita
  • Autoimmune connective tissue disorders: dermatomyositis, systemic lupus erythematosus, subacute cutaneous lupus, chronic cutaneous lupus, diffuse systemic sclerosis (benefit of skin & lung)
  • Others: vasculitis, pyoderma gangrenosum, sarcoidosis, lichen planus

Absolute

  • Hypersensitivity
  • Pregnancy (Category D)

Relative

  • Lactation (excreted in breast milk)
  • Renal/hepatic insufficiency 
  • Cardiopulmonary disease 
  • Peptic ulcer disease 
  • Azathioprine use (Increased risk of bone marrow suppression) 
  • Drugs that interfere with enterohepatic circulation (e.g. cholestyramine)

Dose dependant

  1. Gastrointestinal (#1 side effect): Nausea, vomiting, diarrhea, soft stool, abdominal cramps
  2. Hematological: Neutropenia, anemia, thrombocytopenia, agranulocytosis, neutrophil dysplasia (Pseudo Pelger-Huet anomaly)

Carcinogenicity

  • Lymphoproliferative disorder (in transplant patients), controversial risk of non-melanoma skin cancers

Infections

  • viral, bacterial, mycobacterial, fungal

Gastro-urinary

  • Dysuria, urgency, sterile pyuria, burning 

Neurologic

  • Tinnitus, weakness, headache 

Teratogenicity

  • Ear, facial & distal limb anomalies, heart/ kidneys/esophagus anomalies

Decreased Gastrointestinal absorption of Mycophenolate Mofetil 

  • Antacid, proton pump inhibitors, iron

Decreased Enterohepatic circulation of Mycophenolate Mofetil  (↓Mycophenolic acid serum levels)

  • Trimetrexate, cholestyramine, antibiotics (cephalosporin, fluoroquinolones, penicillin, macrolides, sulfonamide), cyclosporine

Increased Mycophenolic acid serum level

  • Salicylates, probenecid, antivirals, tacrolimus

Mycophenolate Mofetil ↑serum levels of the following drugs

  • Cyclosporine, ganciclovir, acyclovir, phenytoin, theophylline

Baseline

  • Complete blood count, chemistry profile, liver functions tests, urinalysis
  • Pregnancy test
  • Hepatitis B & C serology 
  • Tuberculin skin test

Follow-up

  • Complete blood count, chemistry profile, liver functions tests (every 2-4 weeks after dose escalation & every 2-3 months once dose is stable)

Note:

  • Requires at least 6-8 weeks for response