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Monday, 23 January 2012

New Drug Approvals 2012 - Pt. I - Glucarpidase (VoraxazeTM)




ATC code: V03AF09

The first FDA new drug approval of 2012 is Glucarpidase, approved on Jan 17th 2012. Glucarpidase (tradename: Voraxaze; formerly known as carboxypeptidase-G2 or CPG2) is a carboxypeptidase enzyme indicated for the treatment of toxic plasma methotrexate (MTX) concentrations (>1 umol/L) in patients with delayed MTX clearance due to impaired renal function.

MTX (ChEMBL: CHEMBL426) is an antifolate drug and is one of the most widely used anticancer agents. Unlike other anticancer agents, MTX can be safely administrated over a wide dose range. However, during treatment with high doses of MTX, patients may develop renal dysfunction. Since MTX is primarily cleared by renal excretion, this will lead to toxic levels of MTX. Glucarpidase acts by converting MTX to its inactive metabolites 2,4-diamino-N10-methylpteroic acid (DAMPA) and glutamic acid, providing thus an alternate route of elimination to renal excretion.

Glucarpidase (Uniprot: P06621) is a carboxypeptidase produced by recombinant DNA technology in genetically modified Escherichia coli. Glucarpidase is a 390-amino acid homodimer protein with a molecular weight of 83 kDa. The crystal structure of Glucarpidase is known (PDBe: 1cg2, homotetramer form).


>Glucarpidase
ALAQKRDNVL FQAATDEQPA VIKTLEKLVN IETGTGDAEG IAAAGNFLEA ELKNLGFTVT
RSKSAGLVVG DNIVGKIKGR GGKNLLLMSH MDTVYLKGIL AKAPFRVEGD KAYGPGIADD
KGGNAVILHT LKLLKEYGVR DYGTITVLFN TDEEKGSFGS RDLIQEEAKL ADYVLSFEPT
SAGDEKLSLG TSGIAYVQVN ITGKASHAGA APELGVNALV EASDLVLRTM NIDDKAKNLR
FNWTIAKAGN VSNIIPASAT LNADVRYARN EDFDAAMKTL EERAQQKKLP EADVKVIVTR
GRPAFNAGEG GKKLVDKAVA YYKEAGGTLG VEERTGGGTD AAYAALSGKP VIESLGLPGF
GYHSDKAEYV DISAIPRRLY MAARLIMDLG AGK

The recommended dosage of Glucarpidase is a single intravenous injection of 50 Units/kg.

Glucarpidase has a volume of distribution (Vd) of 3.6 L, a systemic clearance (CL) of 7.5 mL/min and an elimination half-life (t1/2) of 5.6 hours.

The full prescribing information of Voraxaze can be found here.

The license holder is BTG international Inc.

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