Pemetrexed disodium (Eli Lilly).

Abstract

Pemetrexed, a thymidylate synthase (TS) and transferase inhibitor, is in phase III trials with Eli Lilly as a potential treatment for several common solid tumors, including non-small cell lung cancer (NSCLC) and mesothelioma [321789], [410731]. Studies on pemetrexed have concluded that not only is the compound a TS inhibitor but also a potent inhibitor of human dihydrofolate reductase (DHFR). The results suggest that pemetrexed acts upon multiple intracellular targets and that the antitumor effect may be derived from its simultaneous inhibition of multiple folate-requiring enzymes [203662]: this compound has been designated as a multitargeted antifolate (MTA) [386680]. The drug also causes concentration- and time-dependent apoptosis [284380]. Other studies in which the 4-oxo group of the pyrimidine ring portion of pemetrexed was replaced with a hydrogen atom, demonstrated that the resulting analogs were potent DHFR inhibitors with very little activity against the enzymes glycinamide ribonucleotide formyltransferase (GARFT) and TS [310674]. In phase II European studies in 64 patients with advanced breast cancer, encouraging responses were seen in anthracycline-failure (23%) and anthracycline-refractory (19%) patients. Responses were observed in 28% of patients who had been previously treated with a taxane [326097]. Data from a phase II trial of pemetrexed (500 mg/m2 once every 21 days as a 10 min i.v. infusion) as a salvage therapy in advanced breast cancer showed that supplementation of the treatment regime with folic acid (FA) and vitamin B12 reduced its already manageable and tolerable toxicities [408821], [409650]. At doses of 500 mg/m2, the drug was also safely administered to 35 patients with impaired renal function [409953]. Phase I and II trials have shown that the main side effects include neutropenia, thrombocytopenia, mucositis, nausea and vomiting [203666], [272241]. Princeton University holds the patent rights to this drug under EP-00432677. In June 2001, Lilly expected to launch the product in 2003 [412318]. In February 1999, Lehman Brothers predicted launch of the drug in 2001 [319225]. In February 1999, Deutsche Bank predicted sales of $100 million in 2001 rising to $400 million in 2003 [316821]. In November 1999, Lehman Brothers estimated peak revenues in excess of $1 billion [348368]. By September 2001, Bear Stearns & Co predicted sales of $35 million in 2002, rising to $125 million in 2005 [422325].