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Friday, 8 April 2011

New Drug Approvals 2011 - Pt. X Vandetanib (ZactimaTM)








ATC code: L01XE12

On the 6th April 2011, the FDA approved Vandetanib (trade name: ZactimaTM, ATC code: L01XE12, NDA 022405), a multi-kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. (medullary thyroid cancer; CRUK Thyroid cancer; ICD C73) Medullary thyroid cancer is a rare form of Thyroid cancer, but is associated with poorer prognosis. While the primary tumor can be successfully removed using surgery and radiotherapy, and thus can have a high 5 and 10 year survival rate (>90%), the metastatic disease remains challenging and is has a low 40% survival rate. Medullary thyroid cancer can be a sporadic or hereditary disease, and has complex underlying genetic causes. Approximately 25% of cases are associated with the RET (REarranged during Transfection) proto-oncogene. RET mutations cause Multiple Endocrine Neoplasia type 2 (MEN 2) which increases the risk of Thyroid cancer. (see OMIM for MEN 2A and MEN 2B)

Vandetanib (also known as ZD-6474 and Trade name:ZactimaTM) ( IUPAC:N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine); InChI:1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27) SMILES:COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC4CCN(C)CC4 ChEMBL:24828; ) It has the molecular formula C22H24BrFN4O2 and has a molecular weight of 475.36. It has no chiral centres. Vandetanib contains an aminoquinazoline, a very common group within a large number of protein kinase inhibitors - this mimics the adenine ring of ATP.

Vandetanib has been issued with a black box warning because it can prolong QT interval (the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A prolonged QT interval is a biomarker for ventricular tachyarrhythmias like torsades de pointes and a risk factor for sudden death.) For this reason, Vandetanib should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome.

Vandetanib tablets for daily oral administration are available in two dosage strengths, 100 mg and 300 mg, containing 100 mg and 300 mg of vandetanib, respectively. The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterized by a mean clearance (Cl) of approximately 13.2 L/h, a mean volume of distribution of approximately 7450 L, and a median plasma half-life (T1/2) of 19 days.

Vandetanib has a broad activity profile, showing activity against multiple tyrosine kinases including RET (Uniprot: P07949; canSAR Target Synopsis) , EGFR (Uniprot: P00533; canSAR Target Synopsis), FGFR1 (Uniprot: P11362; canSAR Target Synopsis), FGFR2 (Uniprot: P21802; canSAR Target Synopsis), FGFR3 (Uniprot: P22607; canSAR Target Synopsis), and many others, all of which are members of the Protein Tyrosine Kinase family (PFAM:Pkinase_Tyr (PF07714)). RET mutations associated with medullary thyroid cancer include C634R germline mutation in exon 11 and an additional somatic mutation (at chromosomal position 164761.0012), but the efficacy of Vandetanib is independent of the mutation status of RET. A complex structure of Vandetanib bound to RET is available (PDB code: 2ivu @PDBe)

The prescribing information can be found here

Vandetanib is a product of AstraZeneca

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