Pharmaceutical development of the novel arsenical based cancer therapeutic GSAO for Phase I clinical trial.

Abstract

The novel organoarsenical GSAO, 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid, has potential anti-angiogenic capability with application in cancer where tumour metastasis relies on neo-vascularisation. As GSAO arsenic is trivalent, the arsenoxide moiety reacts with appropriately spaced cysteine residues on adenine nucleotide translocase (ANT) mitochondrial membrane protein. Molecular oxidation of the arsenic to the pentavalent structure, as in the degradant GSAA (4-(N-(S-glutathionylacetyl)amino) phenylarsonic acid), prevents sulphydryl interaction and risks abolition of activity. We report here on formulation studies aiming to produce a parenteral product with the primary objective of restricting GSAA transformation from GSAO to protect maximal potency of the molecule. Successful anti-oxidant strategy primarily came from pH control. The presence of glycine was proposed to form a stabilising five-membered oxazarsolidinone ring with arsenoxide and this was investigated using potentiometric assays. We report on these tritration studies identifying a pK(a) of 8.2 associated with an As-OH, but not confirming ring presence. An original clinical trial pharmaceutical was successfully realised by lyophilisation of 50 mg/mL GSAO in 100 mM glycine solution, pH 7 to obtain a 48-month shelf life for the freeze-dried vials. The Phase I clinical study is ongoing in patients with solid tumours refractory to standard therapy.

• Authors: M A Elliott, S J Ford, E Prasad, L J Dick, H Farmer, P J Hogg, G W Halbert
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 426 Issue 1-2 Pg. 67-75 (Apr 15 2012) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 22286018 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• 4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide
• Angiogenesis Inhibitors
• Antioxidants
• Arsenicals
• Glutathione
• Glycine

Topics

• Angiogenesis Inhibitors (administration & dosage, chemistry, therapeutic use)
• Antioxidants (chemistry)
• Arsenicals (administration & dosage, chemistry, therapeutic use)
• Calorimetry, Differential Scanning
• Chemistry, Pharmaceutical
• Drug Compounding
• Drug Stability
• Freeze Drying
• Glutathione (administration & dosage, analogs & derivatives, chemistry, therapeutic use)
• Glycine (chemistry)
• Humans
• Hydrogen-Ion Concentration
• Infusions, Intravenous
• Neoplasms (blood supply, drug therapy)
• Neovascularization, Pathologic (prevention & control)
• Oxidation-Reduction
• Potentiometry
• Technology, Pharmaceutical (methods)
• Time Factors