Pralatrexate Pharmacology and Clinical Development

Abstract

Folates are well known to be essential for many cellular processes, including cellular proliferation. As a consequence, antifolates, the fraudulent mimics of folic acid, have been shown to be potent therapeutic agents in many cancers. Over the past several decades, efforts to improve on this class of drugs have met with little success. Recently, one analog specifically designed to have high affinity for the reduced folate carrier, which efficiently internalizes natural folates and antifolates, has been shown to be very active in T-cell lymphoma. Pralatrexate, approved by the U.S. Food and Drug Administration in 2009, is highly active across many lymphoid malignancies, including chemotherapy-resistant T-cell lymphoma. Emerging combination studies have now shown that pralatrexate is highly synergistic with gemcitabine, histone deacetylase inhibitors like romidepsin and bortezomib. These insights are leading to a number of novel phase I and II combination studies which could challenge existing regimens like CHOP, and improve the outcome of patients with T-cell lymphoma Clin Cancer Res; 19(24); 6657-61. Ó2013 AACR.

The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

“…Numerous other antifolates have since been synthesized and tested preclinically, in many cases drawing from the enhanced understanding of the pharmacology and biology of MTX or AMT, including their membrane transport, polyglutamylation, and binding to intracellular targets. In recent years, a new generation of clinically relevant antifolates has emerged including PDX Thompson, 2009;Marchi et al, 2013), RTX (Wilson and Malfair Taylor, 2009), and PMX (Hazarika et al, 2005;Cohen et al, 2009) (Fig. 1).…”

“…The net result was increased drug efficacy toward leukemia, breast cancer, and nonsmall-cell lung cancer cell lines in vitro and in vivo. In phase I and phase II trials, including patients with non-small-cell lung cancer (Krug et al, 2003) and peripheral T-cell lymphoma (O'Connor et al, 2009;Marchi et al, 2013), PDX showed efficacy and safety. The Food and Drug Administration (FDA) approved the use of PDX in 2009 for the treatment of relapsed, refractory peripheral T-cell lymphoma (Thompson, 2009).…”

Belinostat for the treatment of T-cell lymphoma

“…Many of these agents have demonstrated limited to no activity in B-cell malignancies while demonstrating marked activity in T-cell lymphoma. One such example is pralatrexate (Folotyn Ò ), which was the first drug approved for patients with relapsed or refractory PTCL in 2009 [1][2][3][4].…”

A phase 1 clinical trial of sequential pralatrexate followed by a 48‐hour infusion of 5‐fluorouracil given every other week in adult patients with solid tumors

“…6 Pralatrexate (PDX) is a 10-deaza-aminopterin antifolate that was rationally designed to improve cellular uptake and intracellular retention compared with MTX. [7][8][9][10][11][12][13] It enters cancer cells via the reduced folate carrier (RFC-1), which is overexpressed in cancer cells compared with normal cells. PDX is a high-affinity substrate for RFC-1, and it is more efficiently taken into cells at a rate 14 times greater than MTX.…”

“…The recommended phase 2 doses of single-agent PDX given every other week in trials of patients with nonhematologic malignancies have ranged from 150 mg/m 2 to 190 mg/m 2 with vitamin supplementation. 13,[18][19][20] The initial generation of trials evaluating either MTX or trimetrexate with 5-FU used bolus 5-FU, which is less effective compared with infusional schedules. An every-other-week schedule of leucovorin-modulated 5-FU has been widely tested, and is reported to be well tolerated.…”