Mycophenolic acid

Mycophenolic acid
Systematic (IUPAC) name
(4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid
Clinical data
Trade names CellCept, Myfortic
AHFS/Drugs.com Multum Consumer Information
MedlinePlus a601081
Licence data EMA:Link, US FDA:link
  • AU: D
  • US: D (Evidence of risk)
Oral, intravenous
Pharmacokinetic data
Bioavailability 72% (sodium),
94% (mofetil)[1]
Protein binding 82–97%[1]
Metabolism Hepatic[1]
Half-life 17.9±6.5 hours[1]
Excretion Urine (93%),
faeces (6%)[1]
Identifiers
24280-93-1 Yes
L04AA06
PubChem CID 446541
DrugBank DB01024 Yes
ChemSpider 393865 Yes
UNII HU9DX48N0T 
KEGG D05096 Yes
ChEBI CHEBI:168396 Yes
ChEMBL CHEMBL866 Yes
Chemical data
Formula C17H20O6
320.34 g/mol
  (what is this?)  (verify)
Mycophenolate mofetil
Systematic (IUPAC) name
2-Morpholin-4-ylethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate
Clinical data
Trade names CellCept
AHFS/Drugs.com monograph
Licence data EMA:Link, US FDA:link
  • as above
Identifiers
128794-94-5 Yes
L04AA06
PubChem CID 5281078
DrugBank DB00688 Yes
ChemSpider 4444535 Yes
KEGG C07908 Yes
ChEBI CHEBI:8764 
ChEMBL CHEMBL1456 Yes
Chemical data
Formula C23H31NO7
433.49474 g/mol
  (what is this?)  (verify)

Mycophenolic acid (INN, BAN and USAN) /ˌmaɪkoʊfɨˈnɒlɪk/ (less accurately called mycophenolate) is an immunosuppressant drug used to prevent rejection in organ transplantation. It inhibits an enzyme needed for the growth of T cells and B cells. It was initially marketed as the prodrug mycophenolate mofetil (MMF) to improve oral bioavailability. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is commonly marketed under the trade name CellCept (Roche), and mycophenolate sodium as Myfortic (Novartis).

Clinical use

Indications

Mycophenolate is used for the prevention of organ transplant rejection. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and renal transplant rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of renal transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver, heart, and/or lung transplants in children older than two years.[2]

An immunosuppressant that has drastically decreased the incidence of acute rejection in solid transplant recipients, mycophenolate is increasingly utilized as a steroid sparing treatment in autoimmune diseases and similar immune-mediated disorders including Behçet's disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus,[3] immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis.[4]

Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications[4] compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy.[5] Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects.[5] Walsh et al. even propose that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in patients without renal dysfunction,[6] suggesting that mycophenolate will be encountered more frequently in medical practice.

Comparison to other agents

Compared with azathioprine it has significantly higher incidence of diarrhea, and no difference in risk of any of the other side effects.[7] Mycophenolic acid is 15 times more expensive than azathioprine.[8] The exact role of mycophenolate vs azathioprine has yet to be conclusively established. In long-term immunosuppression, it may be used to avoid calcineurin inhibitors or steroids.

Potential future uses

Mycophenolate mofetil is beginning to be used in the management of auto-immune disorders such as idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), scleroderma (systemic sclerosis or SSc), and pemphigus vulgaris (PV) with success for some patients.[9]

It is also currently being used as a long-term therapy for maintaining remission of granulomatosis with polyangiitis, though thus far, studies have found it inferior to azathioprine. A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro.[10][11]

Takayasu arteritis, ANCA associated vasculitides and all medium vessel vasculitic conditions do respond to it. However, due to its slow onset of action, initial aggressive disease may be managed with high dose steroids and other immunosuppressants. Maintenance of remission is much better with mycophenolate, especially due to lower infection rate with this agent. After persistent remission, dose can be reduced to 1000 mg per day, but not lower as relapses more common in doses lower than this.

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with mycophenolate therapy include diarrhea, nausea, vomiting, joint pain; infections, leukopenia, and/or anemia reflect the immunosuppressive and myelosuppressive nature of the drug. Mycophenolate sodium is also commonly associated with fatigue, headache, cough and/or breathing issues. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis and thrombosis. Infrequent adverse effects (0.1–1% of patients) include esophagitis, gastritis, gastrointestinal tract hemorrhage, and/or invasive cytomegalovirus (CMV) infection.[2] More rarely, pulmonary fibrosis or various neoplasia occur: melanoma, lymphoma, other malignancies having an occurrences of 1 in 20 to 1 in 200, depending on the type, with neoplasia in the skin being the most common site.[12][13] Several cases of pure red cell aplasia (PRCA) have also been reported.[14]

The U.S. Food and Drug Administration (FDA) has issued an alert that patients on mycophenolate mofetil and mycophenolic acid are at increased risk of opportunistic infections, such as activation of latent viral infections, including shingles, other herpes infections, cytomegalovirus, and BK virus associated nephropathy. In addition the FDA is investigating 16 patients that developed a rare neurological disease while taking the drug. This is a viral infection known as progressive multifocal leukoencephalopathy; it attacks the brain and is usually fatal.[15]

Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.[16][17]

GI intolerance in about 10% of patients taking mycophenolate mofetil can be overcome largely by replacing it with mycophenolate sodium or azathioprine.

Blood tests

Among the most common effects of this drug is increased blood cholesterol levels. Other changes in blood chemistry such as hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in BUN are regularly noted.

Pharmacology

Mycophenolate is derived from the fungus Penicillium stoloniferum or in P. echinulatum.[18] Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase,[19] the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes.[20] Other cells are able to recover purines via a separate salvage pathway and are thus able to escape the effect.

Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferative azathioprine. It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin inhibitor (ciclosporin or tacrolimus) and prednisolone.

Chemistry

Mycophenolate mofetil is the morpholino‌ethyl ester of mycophenolic acid; the ester masks the carboxyl group. Mycophenolate mofetil is reported to have a pKa values of 5.6 for the morpholino moiety and 8.5 for the phenolic group.[21]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "CellCept®" (PDF). TGA eBusiness Services. Roche Products Pty Limited. 13 December 2012. Retrieved 25 February 2014.
  2. ↑ 2.0 2.1 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  3. ↑ Boehm I et al. Chilblain lupus erythematosus Hutchinson: successful treatment with mycophenolate mofetil. Arch Dermatol 2001;137:235 – 236 http://archderm.jamanetwork.com/article.aspx?articleid=478189
  4. ↑ 4.0 4.1 Moore RA, Derry S (2006). "Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis". Arthritis Research & Therapy 8 (6): R182. doi:10.1186/ar2093. PMC 1794528. PMID 17163990.
  5. ↑ 5.0 5.1 D'Cruz DP, Khamashta MA, Hughes GR (February 2007). "Systemic lupus erythematosus". Lancet 369 (9561): 587–96. doi:10.1016/S0140-6736(07)60279-7. PMID 17307106.
  6. ↑ Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR (September 2007). "Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis". Clinical Journal of the American Society of Nephrology 2 (5): 968–75. doi:10.2215/CJN.01200307. PMID 17702723.
  7. ↑ Knight SR, Russell NK, Barcena L, Morris PJ (March 2009). "Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review". Transplantation 87 (6): 785–94. doi:10.1097/TP.0b013e3181952623. PMID 19300178.
  8. ↑ Remuzzi G, Lesti M, Gotti E et al. (2004). "Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial". Lancet 364 (9433): 503–12. doi:10.1016/S0140-6736(04)16808-6. PMID 15302193.
  9. ↑ Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thorne JE, Nousari HC (June 2003). "Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil". Archives of Dermatology 139 (6): 739–42. doi:10.1001/archderm.139.6.739. PMID 12810504.
  10. ↑ Diamond MS, Zachariah M, Harris E (2002). "Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA". Virology 304 (2): 211–21. doi:10.1006/viro.2002.1685. PMID 12504563.
  11. ↑ Takhampunya R, Ubol S, Houng HS, Cameron CE, Padmanabhan R (July 2006). "Inhibition of dengue virus replication by mycophenolic acid and ribavirin". The Journal of General Virology 87 (Pt 7): 1947–52. doi:10.1099/vir.0.81655-0. PMID 16760396.
  12. ↑ http://reference.medscape.com/drug/cellcept-myfortic-mycophenolate-343209#4
  13. ↑ http://www.bnf.org
  14. ↑ "CellCept (mycophenolate mofetil) August 2009". U.S. Food and Drug Administration. August 14, 2009. Retrieved 2009-08-21.
  15. ↑ "CellCept (mycophenolate mofetil) August 2009". U.S. Food and Drug Administration. August 14, 2009. Retrieved 2009-08-21.
  16. ↑ "FDA Issues Second CellCept Warning". newsinferno.com. 2008-05-18. Retrieved 2010-10-26.
  17. ↑ "MedWatch Safety Alerts for Human Medical Products". fda.gov. May 2008. Retrieved 2010-10-26.
  18. ↑ Anderson, HA; Bracewell, JM; Fraser, AR; Jones, D; Robertson, GW; Russell, JD (December 1988). "5-Hydroxymaltol and mycophenolic acid, secondary metabolites from Penicillium echinulatum" (PDF). Transactions of the British Mycological Society 91 (4): 649–651. doi:10.1016/S0007-1536(88)80040-8.
  19. ↑ Fulton B, Markham A. "Mycophenolate mofetil : a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation." Drugs. 1996, 51(2):278-98.
  20. ↑ Ransom JT (December 1995). "Mechanism of action of mycophenolate mofetil". Therapeutic Drug Monitoring 17 (6): 681–4. doi:10.1097/00007691-199512000-00023. PMID 8588241.
  21. ↑ http://www.rocheusa.com/products/cellcept/pi.pdf