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Thursday, 1 October 2009

New Drug Approvals - Pt. XIX - Pralatrexate (Folotyn)



Also approved on September 25th was Pralatrexate (tradename Folotyn). Pralatrexate is the first drug approved for the treatment of Peripheral T-Cell Lymphoma (PTCL), an aggressive form of non-Hodgkins lymphoma. Lymphoma is a cancer that begins in the lymphocytes of the immune system. PTCL is a rare disease, occurring in around 9,500 patients each year in the United States.
Pralatrexate, also known as PDX, is a folic analog that competitively inhibits dihydrofolate reductase (DHFR). Since Pralatrexate blocks the use/function of a metabolite, it is also an antimetabolite. Pralatraxate has high affinity for the folate transporter SLC19A1 (also known as RFC-1), and so is an example of a drug that is 'actively transported', and is also a substrate for polyglutamation by the enzyme folylpolyglutamate synthase (FPGS). Once polyglutamated Pralatrexate has a prolonged intracellular half-life, giving prolonged action in malignant cells. Pralatrexate is related to several other drugs, most notably Methotrexate, and 'old' launched drug, and also the clinical stage compounds - Ketotrexate, Edatrexate, and also the antiprotozoal agent Trimetrexate, all of which are DHFR inhibitors.
Pralatrexate is a polar, racemic small molecule (Molecular Weight of 477.5 g.mol-1), soluble in aqueous solutions. Pralatrexate is a mixture of diastereomers (stereoisomers that are not enantiomers, i.e. they are non-superimposable). Diastereomers can have different physical properties biological activities, and different reactivity. Pralatrexate has a volume of distribution (Vd) of 105L and 37L for the S- and R-diastereomers, respectively, a plasma protein binding (ppb) of 67%, a systemic clearance of 417 mL.min-1 (S-diastereomer) and 191 mL.min-1 (R-diastereomer), and an elimination half-life (T1/2)of 12-18 hours. Pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases, and has low potential to induce or inhibit the activity of CYP450 isozymes - elimination is primarily of unchanged drug in urine.
The recommended dosing of Pralatrexate is 30 mg.m-2 administrated as an intravenous injection once weekly for 6 weeks in 7-week cycles. The full prescribing information can be found here.

The structure (2S)-2-[[4-[(1RS)-1-[(2, 4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid is a folate analog in which the hydroxyl group of the pyrimidine ring has been replaced by an amine, and the central amino group of the molecule has been replaced by a stereocenter carbon with a methylacethylene attached to it (which may undergo nucleophilic atack). Pralatrexate diastereomers differ in configuration at this stereocenter only, and so they are also epimers.
<CHEMBL_DRUG>
<DRUG_NAME="Pralatrexate" TRADEMARK_NAME="Folotyn" APPROVAL_DATE="25-SEPT-2009" DRUG_MOLECULAR_WEIGHT=477.5>
<DRUG_STRUCTURE>
<DRUG_SMILES="O=C(O)[C@@H](NC(=O)c1ccc(cc1)C(CC#C)Cc2nc3c(nc2)nc(nc3N)N)CCC(=O)​O">
<InChI="InChI=1/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18
(27-15)19(24)29-23( ​25)30-20)12-4-6-13(7-5-12)21(33)28-16
(22(34)35)8-9-17(31)32/h1,4-​ 7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,3​ 0)/t14?,16-/m0/s1">
<InChIKey="OGSBUKJUDHAQEA-WMCAAGNKSA-N">
</DRUG_STRUCTURE>
<ChemDraw="Pralatrexate.cdx">
<DRUG_TARGET>
VGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFSI
PEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSSV
YKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKFE
VYEKND
</DRUG_TARGET>
</CHEMBL_DRUG>
The license holder is Allos Therapeutics, Inc. and the product website is www.folotyn.com.

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