Drug Abstract for Pralatrexate

Pralatrexate (trade name Folotyn) is a folate analogue inhibitor of dihydrofolate reductase (DHFR) indicated as a single agent used for the treatment of patients with relapsed or refractory Peripheral T-cell lymphoma (PTCL), a form of cancer that develops from T-cells. The ideal dosage is 30mg/m2, once a week for six out of every seven weeks along with vitamin B12 and folic acid supplementation. ‘ Folotyn is a structural analogue of methotrexate and was rationally designed to have increased cellular uptake and retention.' It was originally discovered by Memorial Sloan-Kettering Cancer Center along with Stanford and Southern Research Institute (SRI), and later transferred to Allos Therapeutics for further development. In the 1950s, SRI began research on antifolates with the aim of destroying cancerous cells. ‘In the late 1970s, researchers from Memorial Sloan-Kettering Cancer Center discovered that cancerous cells take in natural folate through a plasma membrane transporter known as reduced folate carrier type 1 (RFC-1).' Further studies showed that when normal cells evolve into cancerous cells they overproduce RFC-1 to ensure they get enough folate. For this reason, the aforementioned research institutes collaborated with the intent of developing an antifolate that has greater therapeutic selectivity, can be transported via RFC-1, and would be more toxic to cancer cells than normal ones. This collaboration led to the identification of pralatrexate in the late 1990s, which was later licensed to Allos Therapeutics for further development.

The mechanism of action for pralatrexate is to competitively inhibit dihydrofolate reductase, the enzyme overexpressed in cancerous cells. ‘The drug first enters the cancer cell by RFC-1. After entry inside the cell, pralatrexate is then polyglutamated by Folylpolyglutamate synthase (FPGS), leading to cellular retention.' Pralatrexate and its polyglutamated counterpart together inhibit DHFR, which leads to interference with the DNA synthesis (e.g depletion of thymidine), and ultimately apoptotic tumor cell death. The polyglutamation of pralatrexate more specifically creates a more efficient influx into the cell via the RFC-1, as well as retention within the cell. ‘This makes pralatrexate more active than other anti-folates such as metrotrexate that is aimed at tumor regression because it is a better substitute for RFC-1 and FPGS.' ‘Besides treatment of PTCL, pralatrexate also received FDA approval for the treatment of other forms of cancer such as lung cancer, bladder cancer, and B-cell lymphoma.'

The pharmacokinetic properties of pralatrexate was evaluated in ten patients with PTCL using the effective dose of 30mg/m2 intravenously over 3-5 minutes, once weekly for six weeks in seven week cycles. ‘For the absorption of the drug, the clinical evaluations showed a total systemic