Dr. Prem Mohan Jha presented on mycophenolate mofetil (MMF) and azathioprine, two immunosuppressive medications used in kidney transplant recipients. MMF is an prodrug of mycophenolic acid that is absorbed and converted in the liver. It is generally well tolerated though can cause gastrointestinal side effects. While azathioprine is older and less used now, both work by inhibiting purine synthesis and interfering with RNA and DNA synthesis to prevent rejection. Monitoring is important due to potential adverse effects like leukopenia.

1. Presenter – Dr Prem Mohan Jha
DNB Nephrology Resident
Max Super Speciality Hospital, Vaishali.

3.  Introduced into clinical transplantation in 1995.
 MMF is a Prodrug.
 Active compound is Mycophenolic Acid (MPA).
◦ Fermentation product of several Penicillium Species.
 Mofetil moiety serves to markedly improve its oral
bioavailability.
 An Enteric-Coated form of MPA (Myfortic) became
available in 2004.

5.  Generally well tolerated and ‘‘user-friendly’’
 CellCept : 250-mg and 500-mg capsules.
◦ Standard dose is 1 g BD.
 Myfortic :180-mg and 360-mg capsules.
◦ Standard dose : 720 mg BD.

6.  Orally administered.
 Rapidly absorbed.
 Hydrolyzed to MPA in the liver.
 Peak level in 1 to 2 hours.
 MPA is then glucuronidated to an inactive form.
 Bioavailability of MMF in the capsule form is 90%,
with a half-life of 12 hours.

7.  Most common adverse events are related to GIT.
◦ Diarrhea : 30%
◦ Nausea, Bloating, Dyspepsia, and Vomiting : 20%.
◦ Frank Esophagitis and Gastritis with occasional GI
hemorrhage : 5%.
◦ May be associated with cytomegalovirus (CMV)
infection.

8.  Leukopenia, anemia, and thrombocytopenia.
◦ Frequency similar to azathioprine.
◦ May require dose adjustment.
 Lymphoproliferative disorders
 Opportunistic infections
 Progressive multifocal leukoencephalopathy (PML)
◦ Rare
 Nephrotoxicity, Neurotoxicity, Hepatotoxicity
◦ Not observed.

9.  Congenital malformations including ear
malformations have been reported.
 Should be discontinued before planned pregnancy
in both males and females.

10.  Therapeutic drug monitoring is generally not required
 In the event of side effects, the longer the period of
drug-dose reduction or discontinuation, the greater
is the subsequent incidence of episodes of acute
rejection.
 Hence, the drug should be reintroduced as soon as
possible and the clinical course carefully monitored.

11.  Not metabolized through the CYP3A enzyme
system.
 MMF and azathioprine should not be administered
concomitantly.
◦ Combined hematologic toxicity.
 Cyclosporine lowers MPA concentrations
◦ By decreasing enterohepatic recycling.

12.  MMF should not be administered simultaneously
with antacids, cholestyramine, sevelamer, or oral
 ferrous sulfate.
◦ Decrease intestinal absorption.
 Do not administer with acyclovir and ganciclovir.
◦ Discontinue MMF when there is evidence of
systemic herpes infection.

13.  An imidazole derivative of 6-mercaptopurine.
 It has been used in clinical transplantation for
nearly 40 years.
 With the introduction of MMF, its use has been
discontinued in many programs.

14.  Purine analogue
 Incorporated into cellular DNA.
 Inhibits purine nucleotide synthesis
 Interferes with the synthesis and metabolism of
RNA.
 Valuable in preventing the onset of acute rejection.
 Ineffective in the therapy of rejection episodes.

15.  Hematologic : most important.
◦ CBC : weekly during first month and less
frequently thereafter.
 Discontinue in case of signiicant leucopenia or
thrombocytopenia.
 Hepatitis and Cholestasis.
◦ Reversible elevations in transaminase and
bilirubin.
 Pancreatitis is a rare.
 Azathioprine is converted to inactive 6-thiouric
acid by xanthine oxidase.

16.  Half of orally administered azathioprine is
absorbed.
 Effectiveness is not blood-level dependent.
 Dose :
◦ As primary immunosuppressant :2 to 3 mg/kg.
◦ As adjunctive therapy with a calcineurin inhibitor,
the dose is :1 to 2 mg/kg.

17.  KDIGO guidelines for kidney transplant recipients suggest
that mycophenolate mofetil be the first-line
antiproliferative agent (2B).
 However, it also mentions that, because of the
substantially increased cost of MMF compared with
azathioprine, there is no clear cut net benefit, but a
decision based upon trade-offs is required.
Kidney disease: Improving global outcomes. Transplant work group.
KDIGO Clinical Practice Guidelines for the Care of Kidney Transplant
Recipients. Am J Transplant. 2009;9(Suppl-3):S10–S13.

19.  Similar MPA plasma concentration–time curves were
obtained for both EC-MPS and MMF.
 EC-MPS 720 mg b.i.d. was shown to be bioequiva lent
to MMF 1000 mg b.i.d. in terms of MPA AUC.
 The only significant difference in this study was the
lower incidence of serious GI infections in the EC-MPS
arm (8.8 vs. 16%, p < 0.05).
 Overall, both treatments elicited a similar
pharmacodynamic response.