High Dose Methotrexate - Tweetorial
#Goodman_Heme
Players
MTX (>500 mg/m2)
Leucovorin (folinic acid)
Sodium bicarbonate
Glucarpidase (hopefully not!)
How we make thymidylate (dTMP)
FH2+NADH = FH4 via dihydrofolate reductase (DHFR)
dUMP+FH4 = dTMP via thymidylate synthase (TS)
#Goodman_Heme
Players
MTX (>500 mg/m2)
Leucovorin (folinic acid)
Sodium bicarbonate
Glucarpidase (hopefully not!)
How we make thymidylate (dTMP)
FH2+NADH = FH4 via dihydrofolate reductase (DHFR)
dUMP+FH4 = dTMP via thymidylate synthase (TS)
MOA of MTX
1. Enters cells via reduced folate carried
2. Polyglutamated (MTX-PG)
3. MTX-PG binds DHFR 1,000 fold greater than FA
4. Competitively inhibits conversion of FH2->FH4 via DHFR
5. No FH4 (dUMP+FH4 = dTMP)
6. No dTMP
7. Stops DNA synthesis
8. Cell dies
1. Enters cells via reduced folate carried
2. Polyglutamated (MTX-PG)
3. MTX-PG binds DHFR 1,000 fold greater than FA
4. Competitively inhibits conversion of FH2->FH4 via DHFR
5. No FH4 (dUMP+FH4 = dTMP)
6. No dTMP
7. Stops DNA synthesis
8. Cell dies
High dose MTX disrupts the blood brain barrier (BBB) and is able to penetrate the CNS.
But high dose MTX causes severe/fatal toxicity =
Nephrotoxicity
Myelosupression
Mucositis
Diarrhea
Hepatitis
How do we prevent these toxicities while still treating the CNS???
But high dose MTX causes severe/fatal toxicity =
Nephrotoxicity
Myelosupression
Mucositis
Diarrhea
Hepatitis
How do we prevent these toxicities while still treating the CNS???
Leucovorin
Discovered as growth factor for bacterium Leuconostoc citrovorum (1948)
LV converted to reduced folic acid (FH4)
Does not require DHFR for its function!
LV allows for some purine/pyrimidine synthesis to occur even in presence of DHFR inhibition
Does not cross BBB
Discovered as growth factor for bacterium Leuconostoc citrovorum (1948)
LV converted to reduced folic acid (FH4)
Does not require DHFR for its function!
LV allows for some purine/pyrimidine synthesis to occur even in presence of DHFR inhibition
Does not cross BBB
Urine alkalization (ph > 7)
MTX and its metabolites, including 7-OH-MTX, DAMPA are poorly soluble at an acidic pH.
An increase in urine pH from 6.0 to 7.0 increases the solubility of MTX 5-8 fold
Reduce intratubular crystal formation (precipitation)
MTX and its metabolites, including 7-OH-MTX, DAMPA are poorly soluble at an acidic pH.
An increase in urine pH from 6.0 to 7.0 increases the solubility of MTX 5-8 fold
Reduce intratubular crystal formation (precipitation)
Protocol
Admission
Urine alkalization with NaHCO3 (150 mEq in 1 L)
Wait for urine pH>7
Rx high dose MTX
Leucovorin* (LV) rescue 24 hours later
Monitor MTX levels daily
*LV doesn't cross BBB and rescues body from toxicity.
LV works without DHFR (which is inhibited by MTX)
Admission
Urine alkalization with NaHCO3 (150 mEq in 1 L)
Wait for urine pH>7
Rx high dose MTX
Leucovorin* (LV) rescue 24 hours later
Monitor MTX levels daily
*LV doesn't cross BBB and rescues body from toxicity.
LV works without DHFR (which is inhibited by MTX)
Concomitant meds to avoid (stop 24-48 hours prior to admission)
Direct inhibition of renal excretion:
NSAIDs
Bactrim
Penicillins
Gemfibrozil
Inhibition of BCRP renal transport:
PPIs!
Unclear:
Keppra
Direct inhibition of renal excretion:
NSAIDs
Bactrim
Penicillins
Gemfibrozil
Inhibition of BCRP renal transport:
PPIs!
Unclear:
Keppra
Nomorgrams estimate time-dependent⬇️MTX
Predicts impending toxicity.
Glucarpidase =
Recombinant bacterial carboxypeptidase
Cleaves MTX = DAMPA + glutamate
⬇️plasma MTX 97% in 15 min
No effect intracellular MTX so continue leucovorin!
LV substrate for GP administer 2 hrs after
Predicts impending toxicity.
Glucarpidase =
Recombinant bacterial carboxypeptidase
Cleaves MTX = DAMPA + glutamate
⬇️plasma MTX 97% in 15 min
No effect intracellular MTX so continue leucovorin!
LV substrate for GP administer 2 hrs after
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