1. Guidelines for administering high dose methotrexate (HDMTX) including pre-hydrating patients with IV fluids containing sodium bicarbonate, maintaining urine pH above 6.5, and continuing IV fluids until methotrexate levels are below 1 uM. 2. Methotrexate level monitoring guidelines at 4, 24, 48, and 72 hours and leucovorin rescue protocols based on methotrexate levels to reduce toxicity. 3. Risk factors for close monitoring include ascites, pleural effusions, poor renal function, concurrent nephrotoxic drugs, vomiting during infusion, and previous delayed clearance.

1. Methotrexate TDM
1. Guidelines for administration of high dose methotrexate
Hydration pre-hydrate with sodium bicarbonate beginning the evening prior to administration of
HDMTX
D5W 1/4 NS + Na bicarbonate40mEq/L + KCl 10mEq/L
IV fluids should run at a rate of >100 ml/m2/hr for a minimum of 12 hours prior to
startingHDMTX
Urine pH Check urine pH with each void
A urinary pH>6.5 must be achieved before startingMTX infusion
Maintain until serumMTX level is <1 uM
2. Methotrexate Leucovorin Guidelines
- Obtain MTX levels atthe end of infusion (Hr 4), 24 and 48 hrs from the startof the infusion
4 hr MTX level goal 1000 microM If > 1500 microM, keep IVF rate at 200ml/m2/hr until 24 hr
level known
24 hr MTX level goal < 10 microM Adjust IVF hydration rate and leucovorin per protocol
48 hr MTX level goal < 1 microM If > 1 microM, adjust IVF hydration rate and leucovorin per
protocol
72 hr MTX level goal < 0.1 microM If < 0.1 microM, adjust IVF fluid hydration and leucovorin
per protocol
* if patient has any fluid collection,monitor MTX levels until MTX is below level of detection x 2 days
3. Increased MTX concentrations and leucovorin rescue
MTX level Threshold for action Recommended LV rescue IV fluids (mL/m2/hr)
24 hr < 10uM Protocol leucovorin rescue 150
10.1 - 20.1 uM 100 mg/m2 IV q 6 hrs - startat hr 30 200
20.1 - 30.0 uM 250 mg/m2 IV q 6 hrs - start immediately,
admit patient
200
30.1 - 50.0 500 mg/m2 IV q6 hrs - start immediately,
admit patient
200
> 50 uM Individualised, check that hydration and
alkalnization are adequate, check for
nephrotoxic drugs, check creatinine,
consider glucarpidase
200
48 hr < 1 uM Protocol leucovorin rescue 150
1.1 - 5 uM 30 mg/m2 PO/IV q6 hrs - and keep
checkinguntil MTX level < 0.1 uM
150
5.1 - 10 uM 100 mg/m2 IV q6 hrs - and keep checking
until MTX level < 0.1 uM
200
10.1 - 20 uM 200 mg/m2 IV q6 hrs - and keep checking
until MTX level < 0.1 uM
200
20.1 - 50 uM 500 mg/m2 IV q6 hrs - and keep checking
until MTX level < 0.1 uM
200
> 50 uM Individualized, check that hydration and
alkalinzation are adequate, check for
nephrotoxic drugs, check creatinine,
consider glucarpidase
72 hr < 0.1 uM No further leucovorin - stop checking
MTX levels ***
Stop IV fluids
0.11 - 0.5 uM 15 mg/m2 PO q12 hrs - and keep 100

2. checkinguntil MTX < 0.1 uM
0.51 - 1.0 uM 15 mg/m2 PO q12 hrs - and keep
checkinguntil MTX < 0.1 uM
150
1.1 - 2.0 uM 30 mg/m2 PO/IV q6 hrs - and keep
checkinguntil MTX < 0.1 uM
150
2.1 - 5.0 uM 50 mg/m2 PO/IV q6 hrs - and keep
checkinguntil MTX < 0.1 uM
150
5.1 - 10 uM 100 mg/m2 IV q6hrs - and keep checking
until MTX level < 0.1 uM
150
> 10 uM Individualized, check that hydration and
alkalinization are adequate, check for
nephrotoxic drugs, check creatinine,
consider glucarpidase
4. How longto continue leucovorin
- Initiatewithin first48 hours
- Until MTX conc < 0.01 uM in patients athigh risk for toxicity
5. High risk factors for closetherapeutic monitoringof MTX
Ascites/pleural effusions - Third spacing
Poor renal function Concurrent therapy with nephrotoxic agents
Patient with emesis during infusion
Patient with delayed clearanceduringprevious course
6. Patient case- HDMTX monitoring
- AS is a 17 - year old male with osteosarcoma.He is receivinghis 3rd courseof HDMTX (12g/m2). He
has previously received 2 courses of cisplatin (120mg/m2 per course)
- End of infusion [MTX] = 1069uM
- 24 hr [MTX] = 19.4 uM
What would you do for AS?
- Begin leucovorin at100mg/m2 IV Q6 hours
- Hydrate at200ml/hr/m2
- Continue to check urinepH until [MTX] < 1uM
- Check [MTX] at48 hrs and adjustleucovorin per guidelines
- Continue to monitor [MTX] until 0.01 uM
(Source from
http://bvsms.saude.gov.br/bvs/publicacoes/inca/farmacocinetica_do_metotrexato_kristine_crews.pd
f)