Severe acute toxicity associated with high-dose methotrexate (MTX) therapy: use of therapeutic drug monitoring and test-dose to guide carboxypeptidase G2 rescue and MTX continuation

The Memorial Sloan Kettering Cancer Center experience with outpatient administration of high dose methotrexate with leucovorin rescue

“…HDMTX has been associated with a number of adverse effects including renal impairment 2, mucositis 1 transient elevation of liver enzymes 3, and leukoencephalopathy 4–7. Since the initiation of monitoring of MTX plasma levels and appropriate alterations in leucovorin dosage and hydration 8–12, the frequency of serious toxicity has decreased and toxic deaths following HDMTX have been reduced 12, although reports in the literature continue to appear 2, 13–16. Acute renal dysfunction, the most common cause of MTX‐associated morbidity and mortality has a reported incidence of 1.8%, with an associated mortality rate of 4% 2.…”

A U–HPLC–ESI–MS/MS–Based Stable Isotope Dilution Method for the Detection and Quantitation of Methotrexate in Plasma

“…This correlation was somewhat unexpected due to reports about the poor specificity of the FPIA method. 12,13 In conclusion, we describe a LC-MS/MS-based method to measure MTX in plasma with minimal sample pretreatment, relative short analysis time, and good performance that can be applied to routine clinical TDM. First, the FPIA might measure higher concentrations because of its nonspecific measurement of MTX metabolites such as DAMPA.…”

“…12,13,33 Recovery based on peak area was moderate with high variance, but this was corrected for by the use of the stable isotope-labeled IS, leading to more reproducible measurements and a recovery of approximately 100%. When measuring very low concentration samples (,100 nM) after very high concentration samples (.50 mM), this could lead to falsely increased MTX concentrations in the low concentration range as was seen when patient samples were measured in random order.…”

Problems of high-dose methotrexatein oncological patients

“…Zato priporo~ajo vsaj 72-urni razmik med aplikacijami prokarbazina in metotreksata (5 e pri visokoodmerni kemoterapiji koncentracije v 42 do 48 urah narastejo nad 10 µmol/l, kot alternativo kalcijevemu folinatu priporo~ajo aplikacijo karboksipeptidaze G2 (CPDG2), ki hidrolizira m e t o t r e k s a t v n e a k t i v n o 2 , 4 -d i a m i n o -N 1 0 -metilpteroinsko kislino (DAMPA) in glutaminsko kislino ter tako `e v nekaj minutah zni`a koncentracijo metotreksata za faktor 1 do 2 na logaritemski skali. Toksi~nost CPDG2 je minimalna, vendar se lahko tako kot pri vseh tujih proteinih pojavijo anafilakti~ne reakcije (20,21).…”