CARBOXYPEPTIDASE-G(2) RESCUE IN A PATIENT WITH HIGH-DOSE METHOTREXATE-INDUCED NEPHROTOXICITY

Background. High dose methotrexate (HDMTX) induced renal failure is a medical emergency, as methotrexate (MTX) is primarily eliminated by re nal excretion. High doses of leucovorin (LV) do not necessarily preven t toxicity in the presence of sustained elevated plasma MTX concentrat ions. The bacterial enzyme carboxypeptidase-G(2) (CPDG(2)) hydrolyzes MTX into inactive metabolites and has been demonstrated to lower plasm a MTX concentrations to nontoxic levels rapidly in the nonhuman primat e after HDMTX infusion. Therefore, CPDG(2) was evaluated as a rescue a gent in a patient with acute renal dysfunction secondary to HDMTX. Met hods. A 16 year old patient with osteosarcoma experienced acute renal dysfunction after HDMTX administration, which resulted in markedly ele vated and sustained plasma MTX concentrations. She received three dose s of CPDG(2) on the fifth day after HDMTX. Plasma MTX concentrations w ere determined before and after CPDG(2) administration. Results. The p lasma MTX concentrations decreased from 60 to 1.2 mu M within 15 minut es after the first dose of CPDG(2). No rebound increase in plasma MTX concentrations or adverse reactions to the enzyme were observed. The p atient developed only mild mucositis. Serum creatinine at the time of CPDG(2) administration was 5 mg/dl and returned to normal within 7 wee ks of enzyme administration. Conclusions. Carboxypeptidase-G(2) rapidl y, markedly, and persistently lowered plasma MTX concentrations to a l evel that could be rescued safely with LV. Based on the experience wit h this patient and on preclinical studies in nonhuman primates, CPDG(2 ) appears to be more effective than hemodialysis or hemoperfusion, and may prove beneficial for patients at risk for life-threatening toxici ty secondary to delayed excretion of MTX.