MMF

Question 1

MMF is a prodrug of what?

Answer 1

MPA = mycophenolic acid

Question 2

Where is MMF converted to MPA (mycophenolic acid)? How is it excreted

Answer 2

MMF -> MPA by esterases in plasma, liver and kidney
MPA inactivated in liver via glucuronidation -> phenolic glucuronide of MPA = MPAG is secreted into bile and recycled to the liver by enterohepatic recirculation maintaining MPAG <=>MPA levels
enzyme that converts MPAG to MPA is beta glucurodinase

Question 3

What is the enzyme that converts MPAG to MPA?

Answer 3

beta glucuronidase (G in MPAG)
high levels in epidermis and GI =>  common s/e

Question 4

what are MMFs peaks plasma levels?

Answer 4

1st peak = 1st hr

2nd - 6-12 hrs, post enterohepatic recycling -> BID dosing

Question 5

t1/2 of MMP?

Answer 5

16-18 hrs in healthy

Question 6

excretion of MMP?

Answer 6

90% in urine, but renal impairment does not have effect on MPA levels

Question 7

what clinical circumstances may cause an increase in MMF -bioavalalbe drug and/or active metabolites leading to a higher risk of infection/other toxicities?

Answer 7

majority of MPA and MPAG bound to albumin
if albumin altered = renal or liver dz, or medications that compete for albumin => decrease MMF dosing
exposure to increased levels of unbound MPA may be a predictor of infection and hematologic toxicity

Question 8

MPA MOA:
what purine biosynthesis enzyme is inhibited
why are activated lymphocytes specifically targeted by MPA?

Answer 8

two mechanisms
1) de novo pathway:
MPA non competitively binds to and inhibits * IMPDH = inoside monophosphate dehydrogenase* (IMP program dehydrogenates inspite of being by the lakes)

MMF has ++ affinity to IMPDH2 of IMPDH that is expressed in activated lymphocytes -> able to target lymphocytes most responsible for disease while having minimal effect on other organ systems

• lymphocytes are completely dependent on de novo pathway
  2) salvage pathway

Question 9

Effect of MMP - what does it do?

Answer 9

inhibits purine biosynthesis
inhibits antibody production by activated B lymphocytes
inhibits fibroblast function (important in tissue fibrosis)
negatively affects dendritic cells
reduces recruitment of inflammatory cells into areas of inflammation by reducing VCAM-1, E-selectins, P-selectins

Question 10

list 6 off label dermatologic uses of MMF?

Answer 10

AICTD
**SLE = especially LUPUS NEPHRITIS
***SSc - great for ILD, some say first line
subacute LE, chilblain LE - decent

DM
bullous:
pemph vulgaris *** GREAT
pemph foliaceous, BP, cicatricial pemph, paraneoplastic, EBA, LABD

Vasculitis
**great for renal dz exp in HSP
Wegener, MPA, Churg, urticarial - hypocomplementemic, Behcet

Mcs
PG, cutaneous Crohns, Sarco, chronic urticaria, LP, LPP, etc

papulosquamous
*PsO - SUCKS
AD - very small studies; 720 BID (
dyshidrotic eczema
chronic actinic derm

Question 11

absolute c/i of MMF?

relative c/i?

Answer 11

pregnancy
drug allergy

relative (basically chest to belly button)
lactation
cardiopulmonary dz
peptic ulcer dz (enteric formulation b/c GI cells collect conversion enzyme beta glucuronidase to send MPAG back to MPA)
hepatic dz (albumin bound or toxic)
renal dz (albumin bound or toxic - and renal decreases albumin)
drugs that interfere with enterohepatic recirculation such as cholestyramine

Question 12

7 adverse effects of MMF?

Answer 12

GI: MC, dose dependent: N/V/D, soft stools, anorexia, abdo cramps, ** anal tenderness
carcinogenicity: lymphoproliferative d/o; NMSCa (controversial)
GU: urgency, frequency, dysuria, **sterile pyuria; does NOT cause nephrotoxicity
Teratogenicity: first trimester loss, facial/ear abnormalities, limb abn, heart, esophagus, kidneys abn

Carcinogenic, heme, infectious, neuro (mood, fatigue)
GI, GU, teratogenic
Heme: dose dependent, reversible: neutropenia, anemia, thrombocytopenia, agranulocytosis, neutrophil dysplasia
Ifnx: viral, bacterial, atypical mycoplasma, fungal
* progressive multifocal leukoencephalopathy - controversial
Neuro: weakness, fatigue, headaches, tinnitus, insomnia, depression, anxiety, mood changes (peds)

GGreaT CHIN**

Question 13

2 s/e of MMF that are dose dependent?

Answer 13

GI and Neuro
nausea, vomiting, diarrhea, cramps, loose stool, anal tenderness
fatigue, headaches, tinnitus, insomnia, depression, anxiety, mood changes

(first and last of GGreaT ChIN)

Question 14

carcinogenic effects of MMF?

Answer 14

controversial, mostly in transplants on 2-3 g daily
cases of lymphoma and lymphoproliferative disorders
conflicting data on NMSCa ? BCC, thought protective for SCC in studies

Question 15

What is the MC category of adverse effects from MMF and what are some specific examples in that category?

Answer 15

GI toxicity is MC
nausea, vomiting, diarrhea, increased stool frequency, abdominal cramping, anal tenderness
GI ULCERATIONS + infections, including CMV
++ severe in transplants: 20-55% of 2-3 g cohort vs 5-10% of pemphigus, improve over time

not hepatotoxic

Question 16

how can you minimize GI s/e of MMF?

Answer 16

take with food
2-3 /day dosing
switching to enteric coated MPS

Question 17

what is the unique form of MMF induced neutrophil dysplasia?

Answer 17

pseudo Pelger- Huet anomaly - left shift of entire CBC and nuclear hypolobulation -> neutropenia may develop, reversible

MA PHt but in bathing suit

Question 18

What dose of MMF leads to increased infections?

Answer 18

> 2 g daily

viral (herpes zoster, herpes simplex), bacterial, atypical myco, fungal

Question 19

What is the likelihood that MMF truly induces progressive multifocal leukoencephalopathy (PML)?

Answer 19

cases of progressive multifocal leukoencephalopathy (PML) associated with MMF occurred in patients with transplanted organs and longstanding SLE on concomitant immunosuppression. It is difficult to know the exact contribution of MMF to the deleloplment of PML

Question 20

Boxed warning regarding pregnancy and MMF?

Answer 20

category D
increased risk of first trimester loss
external ear, facial including cleft lip and palate, distal limb, heart and esophagus, kidney.
MMF embryopathy
must have negative pregnancy test within 1 week before starting and repeat 1 week later.
2 methods of birth control required

Question 21

What is MMF embryopathy?

Answer 21

ear, eye and lip/palate abnormlatities

MMF - > EEP

Question 22

when can one get pregnant post MMF?

Answer 22

contraception 4 weeks before MMF and for 6 weeks post stopping
MAY REDUCE LEVELS OF OCP
excreted in breast milk (lactation c/i)

Question 23

important drug interactions for MMP?

Answer 23

GI is MC S/E -> think GI -> antacid/PPI (1 hr needed)

antacids/PPIs reduce MPA levels
calcium inhibits absorption of MMP 
separate each by at least 1 hr
do not use with bile acid sequestrants
***studies about levonorgestrel decrease with MMP (OCP)

Question 24

which medications can increase the toxicity of MMF by inhibiting renal tubular excretion of MPA?

Answer 24

antiviral meds acyclovir, ganciclovir and valganciclovir - inhibit renal tubular secretions -> increased MPA levels
valacyclovir and MMP may increase risk of neutropenia (one report)

MMP reduces the level of nevirapine antiviral

Cs and CsA reduce MMF serum levels

administration of live vaccines not recommended

Question 25

what is the typical starting dose of MMF? therapeutically effective dose of MMF?

Answer 25

2-3 g divided BID;
also myfortic = EC MPA is available in 360/720 mg EC tablets - 720 mg EC BID is equivalent to 1g BID for MMF

start: 500 mg x OD QHS x 1 week -> 500 mg BID -> increase in 500 mg increments Q2-4 days until 1.5 mg BID (max dose if needed)

onset 6-8 WEEKS

available in 250, 500 and oral solution of 100 mg/ml

Question 26

MMF monitoring?

Answer 26

pre:
complete physical
CBCd, Cr, BUN, lytes, LFTs, hep B/C, HIV, beta HCG, tuberculin

repeats: CBC, LFTs, Cr Q 2 weeks x 2-3 months until stable, preggo (monthly a consideration)

Question 27

draw out MMF MOA?

Answer 27