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Presentation Of
METHOTREXATE
DIRECTED BY :DR.RAFIQ ABOU SHAABAN.
PRESENTED BY :EMAN SALEM.
ID #:9860152.
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CONTENT :INTRODUCTION : CHEMICAL STRUCTURE.
 BRAND NAME.
 THERAPEUTIC CATEGORY.
 INTRODUCTION OF MTX.
 MECHANISM OF ACTION .
 SIDE EFFECT.
 USES .
 DRUG – DRUG INTERACTION.
 CONTRAINDICATION &ADVESE REACTION.
 THERAPEUTIC PLASMA CONC.
 TOXIC PLASMA CONC .
 GOALS OF MONITORING.
 PHARMACOKINETIC :-
 BIOAVAILABILITY.
 VOLUME OF DISTRIBUTION.
 CLEARANCE .
 HALF – LIFE .
 TIME TO SAMPLE.
 KEY PARAMETERS.
QUESTION & ANSWERS.
Abbreviations:MTX :- METHOTREXATE .
PC :- PLASMA CONCENTRATION.
Pt :- PATIENT
IV :- INTRA VENOUS INGECTION .
VD :- VOLUME DISTRIBUTION .
CONC :- CONCENTRATION .
CL :- CLEARANCE .
T0.5 :- HALF-LIFE .
T.P.C :- THERAPEUTIC PLASMA CONCENTRATION .
T.O.P.C :- TOXIC PLASMA CONCENTRATION .
LCO :- LEUCOVORIN .
SrCr :- SERUM CREATININE .
Cpss ave :- AVERAGE PLASMA CONCENTRATION AT
STEADY STATE .
HRS :- HOURS .
METHOTREXATE
chemical structure:-
Brand Names:- Abitrexate; Folex®; Folex® PFS; Methotrexate®
LPF; Mexate®; Mexate®-AQ; Rheumatrex®
Available Salts :-Methotrexate Sodium
Synonyms:- Amethopterin; Methotrexate Sodium; MTX; NSC-740
Generic Equivalent :-Yes
Therapeutic Category :-
 Antineoplastic Agent, Antimetabolite
Introduction of methotrexate:Methotrexate is one of the oldest chemotherapy drugs. It has been
around and in use for many years. Methotrexate is a yellow powder
which, when prepared for use, becomes a clear, yellow liquid, and is
given by intravenous route. It is also available in tablet form.
Methotrexate (Rheumatrex) is a medicine that is used to treat
rheumatoid arthritis (RA) psoriatic arthritis, Reiter's syndrome, and
other conditions. First developed to treat certain types of cancer,
methotrexate is routinely used at higher doses as a cancer therapy and
is now used at much lower doses to treat rheumatic diseases, like
rheumatoid arthritis. Methotrexate has been studied for over 20 years
in the treatment of rheumatoid arthritis, and in 1988 was approved for
this use in adults by the U.S. Food and Drug Administration (FDA).
It is most commonly used in the following situations:
 Breast cancer
 Head and Neck cancer
 Lung cancer
 Acute Lymphocytic Leukemia
 Injection inside the spinal fluid
 Gestational Throphoblastic disease
 Bone tumors
 Lymphomas
 Treatment of arthritis
The type and extent of a cancer will determine the method and
schedule of administration of this drug. This decision is made by the
medical oncologist. Methotrexate is normally given intravenously or
orally.
Mechanism of Action:An antimetabolite that binds to dihydrofolate reductase blocking
the reduction of dihydrofolate to tetrahydrofolic acid; depletion
of tetrahydrofolic acid leads to depletion of DNA precursors
and inhibition of DNA and purine synthesis
Side effects:Methotrexate exerts its chemotherapeutic effect by its ability to
counteract and compete with folic acid in cancer cells resulting in folic
acid deficiency within the cells and causing their demise. Normal cells
are not immune form this effect of Methotrexate either. As a result, it
can cause significant side effects in the body. The degree and severity
of the side effects depend on the amount and schedule of the
administration of Methotrexate. Following are some of the most
common and important ill effects:
 Low white blood counts
 Low platelet count








Anemia
Hair Loss
Soreness of the mouth, difficulty swallowing
Diarrhea
Liver damage
Lung damage
Nerve damage
Kidney damage
Most of these complications and side effects of Methotrexate can be
either prevented or treated by using Leucovorin, which is normally
administered 24 hours after the Methotrexate is given. This will allow
the Methotrexate to exert its anti cancer effect. It is imperative that
patients relay any side effects or problems to their medical oncologists.
Use:Oncologic: Treatment of breast, esophageal, gastric, head and neck,
lung and testicular carcinomas; leukemias; lymphomas; soft tissue
sarcomas and osteosarcomas; trophoblastic neoplasms.
Nononcologic: Prophylaxis of rejection for kidney, heart, liver, and
bone marrow transplants; severe rheumatoid disorders; psoriasis;
dermatomyositis.
Drug-Drug Interactions
Cotraindication
ACITRETIN/METHOTREXATE
METHOTREXATE/ASPARAGINASE
Sever
METHOTREXATE/NSAIDS
METHOTREXATE/PROBENECID
METHOTREXATE/PROCARBAZINE
METHOTREXATE/SALICYLATES
METHOTREXATE/SULFONAMIDES
Moderate
DIGOXIN,
ORAL/ANTINEOPLA
STICS
HYDANTOINS/ANTINEOPLASTICS
LEFLUNOMIDE/METHOTREXATE
Food Interaction
Milk-rich foods may decrease MTX absorption;
folate may decrease drug response
Severe
CONTRAINDICATION&ADVERSE REACTION:Contraindications
Precautions
Adverse Reactions
Lactation
. Hypersensitivity to methotrexate.
.severe renal or hepatic impairment.
.severe bone marrow suppression.
.rheumatoid arthritis.
. AIDS.
.blood dyscrasias
. peptic ulcer disease
. ulcerative colitis.
. ascites, and pleural effusion.
. Nausea, vomiting, diarrhea.
. pruritus, , rash, hyperpigmentation of skin.
. anemia, hemorrhage.
. : Blurred vision
. Enters breast milk/contraindicated.
Emetic Potential:50 mg/m2
Very low (<10%):
Low (10% to 30%):
250 mg/m2
Moderate (30% to 60%):
1000 mg/m2
High (60% to 90%): >1000 mg/m2
Methotrexate Dosing Schedules:Dose
Conventional
dose
Intermediate
dose
High dose
Route
15-20 mg/m2 Oral
30-50 mg/m2 Oral, I.V.
15 mg/day
Oral, I.M.
for 5 days
Frequency
Twice weekly
Weekly
Every 2-3 weeks
50-150
I.V. push
Every 2-3 weeks
mg/m2
240 mg/m2* I.V. infusion Every 4-7 days
0.5-1 g/m2* I.V. infusion Every 2-3 weeks
1-12 g/m2*
I.V. infusion Every 1-3 weeks
Pharmacodynamics:Approximate time to benefit in treatment of rheumatoid arthritis: 1-2
months.
Pharmacokinetics:-
Absorption
. Oral: Rapid; well absorbed at low doses (<30 mg/m2);
erratically and incompletely absorbed at larger doses.
. Oral absorption of methotrexate appears to be highly variable
and dose dependent. The bioavailability of methotrexate
decreases with increasing oral doses ) and absorption is
substantially reduced at doses exceeding 80 mg/m2.The poor
bioavailability should be assumed with oral methotrexate doses
of 100 mg/m2 or greater, regardless of the dosage schedule
used.
. I.M.: Completely absorbed.
. The
drug penetrates slowly into third space fluids (ie, ascites,
pleural or pericardial effusions, or CSF) and adipose tissue,
and exits from these compartments slowly; crosses the
placenta; can cross the blood-brain barrier; sustained
concentrations are retained in the kidney and liver .
Distribution
.Small amounts excreted into breast milk& At serum
methotrexate concentrations exceeding 0.1 µmol/mL, passive
diffusion becomes a major
.Protein
binding: 50%
*<10% of dose is metabolized, converted to 4-deoxy-4amino-N10-methyl pteroic acid (DAMPA) by
carboxypeptidase (GI tract), to 7-hydroxymethotrexate by
aldehyde oxidase (liver) and polyglutamated
intracellularly. In the liver to 7-hydroxymethotrexate.
* Time to peak serum concentrations:
Oral: 0.5-4 hours
Metabolism
Parenteral: 0.5-2 hours
 Half-life: Low doses: 3-10 hours
 High doses: 8-12 hours
 Small amounts in feces; primarily
Elimination
 Small amounts in feces ; primarily excreted
unchanged in urine (44%-100%) via glomerular
filteration & active secretion by the renal tubule ;
(1%-11%)of a dose is excrated as the 7-hydroxy
metabolite.
Therapeutic plasma concentration: concentration various neoplasm range from 10-6 up to 10-3 or10-2 molar.
 MTX conc. in the range of 16*10-6 molar are more successful in treatment of
leukemic pt.
 MTX conc.falls below 1*10-7 with in 48hrs. following the initiation of
therapy or dis cotinuated of rescue factor.
Toxic plasma cocenteration: Plasma conc. exceeding 1*10-8 to 10-7 M for 48 hrs. or more è toxicity.
 The most common toxic effects of MTX include myelosuppression ,oral
&gastrointestinal mucositis &acute hepatic dysfunction.
Leucovorin Rescue: In order insure that MTX toxicities don’t occur , rescue factor is administrated
every 4-6 hrs. in doses which rang from 10mg/m2.
 The usually course of rescue therapy is from 12-72 hrs. or until the PC of
MTX falls below critical value of 1*10-7M.
Goals of monitoring: To ensure that all pts. Receive adequate doses of rescue factor to prevent
seriouse toxicity.
 PC monitoring is beneficial in deticting unusall MTX disposition
characteristics that could result in serious toxicity.
MTX assaye: All assay used should have the ability to measure PC bellow rescue value
of 1*10-7M & above 1*10-6M.
 When MTX plasma levels are still elevated at 48 hrs. the dose rescue factor
must be ed .
Bioavailability:-Oral absorption: MTX will absorbed completely &rapid with peak conc.
 occuring in 1-2hrs.following doses of less than 30mg/m2.
 At doses more than 80mg/m2 , the extent of MTX absorption declines &
bioavailability is in complet , for this reson , moderate & ã dose of MTX
regimens must be administrated by I.V rout.
 doses of MTX (less than 30mg/m2) may be administrated parenterally
orally.
Volume of distribution: The relation ship between MTX cp & VD is complex.
 The drug displays at least abi-exponential elemination curve , so the initial
plasma vd of about 0.2 L/Kg & 2nd larger vd of 0.5-1.0 L/kg following
coplete distribution.
-As cp increase  vd will increase , this will reflect : an active transport system , which becomes saturated at cp.
 Allowing passive intracellular diffusion of MTX .
-For multi compartment model :-
 when loading doses are required , a vd of 0.2-0.5L/kg is usually employed.
 presence of third space fluid such as edema or pleural effusions can
influence vd of MTX.
 Although pleural effusions don’t increase VD , the ã conc. of MTX , which
accumulate in these spaces , can be important , because equilibration with
plasma is delayed.
Clearance: The vast majority of MTX is eliminated by the renal rout. MTX CL ranges
from 1 to as mush as 2 times CL.
 The RCL of MTX is also influenced by a # of compounds .
 Since MTX RCL may be inhibited , all drugs should be cautiously to the
regimen of pt. receivingMTX therapy.
 Changes in renal function are important when designing of monitoring
MTX therapy , there fore all pt. Receiving moderate(500-1500mg) &ã
doses(greater than 5gm) MTX therapy should have their plasma level of
MTX & their renal functions monitored.
 While the therapeutic dose of MTX may rang over several gms. ,serious
toxicity & death can occur , from as little as (10mg) of MTX administered to
apt. with inadequate renal function.
 Administration of prostaglandin inhibitors , indomethacie & ketoprofen
with MTX has been associated with an acute äin renal function & a greatly
prolonged exposure to ã MTX conc.
Half-life: The relation ship between MTX’s Vd & CL is complex.
 The t0.5 for MTX results from both a changing Vd & CL , therefore
utilization of traditional linear PK modeling is difficult.
 In 2 compartment model , the terminal or ß t0.5 of about 10 hrs. appears to
represent the elimination phase. It doesn’t become apparent until PC. Decline
in to range of 510-7M (0.5MM).
 Since elimination /terminal phase is independent of the dose administered ,
it reflects the change in distribution & elimination of MTX.
 Elimination phase is important because the retention of even a very small
amount of administered dose can be potentially toxic to the pt.
 The apparent terminal t0.5 of MTX is some what variable , it doesn’t
appear to  with ing dose.
 A very large % of total MTX maybe eliminated during µ phase.
 Pleural effusions can prolong the terminal t0.5 of MTX & Leucovorin
rescue regimens may need to be extended over a longer period of time in this
situation.
Time to sample : The purpose of monitoring MTX PC is 2 fold.
 MTX PC can be used to evaluate the potential efficacy of a given regimen,
to determine if the quantity &/or duration of leucovorin rescue is adequate.
 There are 2 situation when monitoring MTX levels for efficacy are useful.
A)The 1st is in pts. Who are to receive MTX over a sufficiently long time
period so that actual infusion rate can adjusted . B) The 2nd is in pt. who are
going to receive repeated MTX doses in which case future doses can be
adjusted to achieve the desired target conc.
 When using MTX levels to evaluate the rescue dosage regimen samples are
obtained (24-48) hrs. following the initiation of therapy to determine whether
additional leucovorin will be required either in quantity or duration of
administration.
 For pts. With plasma levels below 1*10-7M , aleucovorin rescue dose of
10mg/m2 every 6hrs. is generally adequate to prevent toxicity if continued
until the PC drops below 1*10-7M.
 Plasma samples obtained prior to the critical48 hrs. time period may
indicate whether the elimination of MTX is normal , because of the potential
toxicity associated with even small amount retained MTX , all pts. Should
have proven MTX conc. below 110-7M before leucovorin rescue is
discontinued.
 In most protocols , MTX levels are monitored sometime during the IV
infusion , at 48hrs. & every 24hrs. until levels drop below the conc. at which
the pt. is considered to be rescued usually 110-7M.
KEY PARAMETERS:T.P.C
TO.P.C
F(bioavailability)
*>1*10-7M for >48 hrs.
*(1*10-8 – 1*10-7) at >48 hrs. require Ûed
rescue factor doses continuous CNS MTX
conc. >10-8m.
*D < 30mg/m2.
*D > 80mg/m2.
VD(initial)
* 0.2 L/kg.
VD AUC
* 0.7 L/kg.
CL
* 1.6 (CLcr)
T0.5(PC < 5*10M)
* 3hrs
T0.5(PC > 5*10M )
* 10 hrs.
NOTE:-
 The current dosing regimen of MTX can range from as low as (20 –
50mg) to as high as (10 –12mg) or more over period as shorter as (3 – 6
hrs.) & as long as (40hrs.).
QUESTION & ANSWERES: Q#1 : P.J is a 60 yrs. old , 70 kg male (SrCr =1.2mg/dl) who is to receive
a course of MTX therapy. His regimen will consist of a 30mg MTX
DL to be administered over 10 – 15 min., followed by an IV infusion
of 30mg/hrs for the next 36 hrs. He will then receive a 20mg
(approximately 10mg/m2) dose of leucovorin every 6 hrs. IV for the
1st 4 doses followed by 8 doses orally at 6 hrs. The LCO. Regimen
will begin immediately after the 36 hrs. MTX infusion has been
discontinued & is schedules to continues for the next 72 hrs. , ending
108 hrs. after initiation of the MTX therapy. MTX levels are
scheduling to be obtained 24 hrs. after the beginning of the 30mg/hrs
infusion at 48 hrs.(12 hrs. after the end of the 36 hrs. infusion ).
calculated MTX conc. at the scheduled sampling time :
Solution: CLcr for males = (140-age)(wt) / (72)(Sc Crss)
= (140-60)(72) / (72((1.2)
= 64.48 ml/min.
CLcr (L/min) = [CLcr(ml/min)] [60min/hr / 1000ml/L]
= 3.88 L/hr
CLMTX = 1.6 *CLcr = 1.6 * 3.9 = 6.24 L/hr.
24 hrs conc:Cpss ave = (s)(f)(D/t) / CL = 1*1(30 mg/ hr) / 6.24 L/hr
= 4.8 mg/L.
MTX conc. in 10-6m = MTX conc / 0.454 = 4.8 / 0.454
= 1.057 *10-5.
48 hrs level :cp = cp*e- kdt.
Kd = 0.693 / t0.5 = 0.693 / 3 = 0.231.
Cp = 1* 10-6 *e –(0.231)(12) = 6.25 * 10-7 M .
The 60 hrs level :T = In (10*10-6m) /(0.5*10-6m / 0.231hrs-1 ) = 3 / 0.231 –1
= 13 hrs.
kd = 0.693 / 10hrs = 0.0693 hrs –1 .
cp = cp * e –kdt = 0.5*10-6 e-(0.0693*11) = 2.3*10-7 m.
Q#2: PJ’S MTX level were reported as 8*10-6 m at 24 hrs, 0.5*106mat 48 hrs & 0.3*10-6m at 60 hrs. , how would interpret each of
these MTX values ?
What would be an appropriate course of action regarding p.j.’s
rescue thereby ?
 Evaluating the 24hrs conc . The initial plasma conc. of 8*10-6 is lower than
the predicated conc. calculated in Q1 (10.57*10-6m) . The lower than predicted
conc. suggests that pj. ‘s MTX CL is greater than excepted ; however, the
difference between the predicted & actual concs. Is well with in the excepted
variation.
 Evaluating the 48 hrs conc .The plasma level of 5*10-7 m at 48 hrs. (12 hrs.
after the infusion) suggests that PJ .is progressing as excepted during the initial
elimination phase . The difference between the excepted (6.25*10-7m) &
observed conc. is minimal , considering the fact that the initial plasma level was
slightly lower than predicted . because the observed plasma level is below 1*106 m at 48 hrs. , it is unnecessary to Û the leucovorin dose.
 Evaluating the 60 hrs conc. The measured MTX conc. of 3*10-7 m at 60hrs
is greater than the predicted conc. of 2.3*10-7 m . Although the differences are
not remarkable , it is of some conc. that PJ’S t0.5 is greater than anticipated .
P.J.’S . elimination rate constant & t0.5 are .0.046 hrs. , respectively . These are
calculated from the MTX conc. at 48 hrs. & 60hrs. using equations 28&31 , &
atime interval of 12 hrs.:kd = In (Cp1 / Cp2 ) / t
= In [5*10-7m / 3*10-7m] / 12 =0.0426 hrs-1.
T0.5 = 0.693 / kd
= 0.693 / 0.0426 = 16.3hr.
 Regardless of the cause , it is important to determine whether P.J. will
achieve a plasma conc. of less than 1*10-7 m by the time the LCOV. Rescue is
scheduled to be discontinued.
 Using the pt. specific or revised elimination rate constant of 0.0426 hrs-1 &
equation 4.6 , it appears as though P.J MTX conc. will fall to 1.0*10-7m after an
additional 25 hrs. (85 hrs. after starting the MTX therapy) . This is well before
the time scheduled for the discontinuation of LCOV. (108 hrs. after starting the
MTX infusion ).
T = In(Cp1 / Cp2) / kd
= In[3*10-7m / 1*10-7m] / 0.0426
= 25.8 hr.
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