MMF Flashcards
MMF is a prodrug of what?
MPA = mycophenolic acid
Where is MMF converted to MPA (mycophenolic acid)? How is it excreted
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
What is the enzyme that converts MPAG to MPA?
beta glucuronidase (G in MPAG) high levels in epidermis and GI => common s/e
what are MMFs peaks plasma levels?
1st peak = 1st hr
2nd - 6-12 hrs, post enterohepatic recycling -> BID dosing
t1/2 of MMP?
16-18 hrs in healthy
excretion of MMP?
90% in urine, but renal impairment does not have effect on MPA levels
what clinical circumstances may cause an increase in MMF -bioavalalbe drug and/or active metabolites leading to a higher risk of infection/other toxicities?
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
MPA MOA:
what purine biosynthesis enzyme is inhibited
why are activated lymphocytes specifically targeted by MPA?
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
Effect of MMP - what does it do?
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
list 6 off label dermatologic uses of MMF?
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
absolute c/i of MMF?
relative c/i?
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
7 adverse effects of MMF?
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**
2 s/e of MMF that are dose dependent?
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)
carcinogenic effects of MMF?
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
What is the MC category of adverse effects from MMF and what are some specific examples in that category?
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
how can you minimize GI s/e of MMF?
take with food
2-3 /day dosing
switching to enteric coated MPS
what is the unique form of MMF induced neutrophil dysplasia?
pseudo Pelger- Huet anomaly - left shift of entire CBC and nuclear hypolobulation -> neutropenia may develop, reversible
MA PHt but in bathing suit
What dose of MMF leads to increased infections?
> 2 g daily
viral (herpes zoster, herpes simplex), bacterial, atypical myco, fungal
What is the likelihood that MMF truly induces progressive multifocal leukoencephalopathy (PML)?
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
Boxed warning regarding pregnancy and MMF?
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
What is MMF embryopathy?
ear, eye and lip/palate abnormlatities
MMF - > EEP
when can one get pregnant post MMF?
contraception 4 weeks before MMF and for 6 weeks post stopping
MAY REDUCE LEVELS OF OCP
excreted in breast milk (lactation c/i)
important drug interactions for MMP?
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)
which medications can increase the toxicity of MMF by inhibiting renal tubular excretion of MPA?
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
what is the typical starting dose of MMF? therapeutically effective dose of MMF?
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
MMF monitoring?
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)
draw out MMF MOA?
