Pemetrexed toxicity

Pemetrexed toxicity mirrors that of methotrexate, with the additional feature of a prominent erythematous and pruritic rash in 40% of patients. Dexamethasone, 4 mg twice-daily on days —1, 0, and +1, markedly diminishes this toxicity. Unpredictably severe myelosuppression with pemetrexed, seen especially in patients with preexisting homocystinemia and possibly reflecting folate deficiency, is largely eliminated by concurrent administration of low doses o/folic acid, 0.35—1 mg/day beginning 1—2 weeks prior to pemetrexed and continuing while the drug is administered. Intramuscular vitamin Bj2(I mg) is given with the first dose of pemetrexed to correct possible Bj2 deficiency. There is no evidence that these small doses of folate and Bj compromise the therapeutic effect. 

Oral folic acid and intramuscular vitamin B12 has been reported to not alter the pharmacokinetics of pemetrexed and because these vitamins were found to decrease pemetrexed toxicity, it is recommended that all patients receiving pemetrexed should receive folic acid and Bj2 supplements. - ... 

Pharmacogenetics may influence the response to antifolates and their toxicity. A mutation in methylenetetrahydrofolate reductase, the enzyme that generates methylenetetrahydrofolate cofactor for TS, reduces its activity and thereby increases methotrexate toxicity. The presence of this polymorphism in leukemic cells confers increased sensitivity to methotrexate, and may also modulate the toxicity and therapeutic effect of pemetrexed, a predominant TS inhibitor. Likewise, polymorphisms in the promoter region of TS affect its expression, and by altering the intracellular levels ofTS, modulate the response and toxicity of both antifolates and fluoropyrimidines. 

The US manufacturers state that there is no pharmacokinetic interaction between pemetrexed and cisplatin, but there is the possibility that cispla-tin-induced nephrotoxicity could decrease pemetrexed clearance and increase its toxicity. However, it should be noted that the use of pemetrexed with cisplatin is indicated for mesothelioma. - ... 

The manufacturers consider that the eoneurrent use of nephrotoxic drugs could potentially decrease the elearanee of pemetrexed and therefore increase its toxicity. - In the UK, the manufacturer specifically mentions aminoglycosides, loop diuretics, platinum compounds (see also (a) cisplatin above) and ciciosporin, and recommends caution with combined use, and, if necessary, close monitoring of creatinine clearance. ... 

Sweeney CJ, Takimoto CH, Latz JE, Baker SD, Muny DJ, Krull JH, Fife K, Battiato L, Cleverly A, Chaudhary AK, Chaudhuri T, Sandler A, Mita AC, Rowinsky EK. Two drug intemctic i studies evaluating the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in patients with advanced cancer. Cfiw Cancer Res (2006) 12, 536-42. 

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