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New Drug Approvals - Pt. XVII - Telavancin (Vibativ)

By jpo
The latest new drug approval, on 11th September 2009 was Telavancin - which was approved for the treatment of adults with complicated skin and skin structure infections (cSSSI) caused by susceptible Gram-positive bacteria, including Staphylococcus aureus, both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains. Telavancin is also active against Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus) and Enterococcus faecalis (vancomycin susceptible isolates only). Telavancin is a semisynthetic derivative of Vancomycin. Vancomycin itself is a natural product drug, isolated originally from soil samples in Borneo, and is produced by controlled fermentation of Amycolatopsis orientalis - a member of the Actinobacteria.

Telavancin has a dual mechanism of action, firstly it inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycan - the mesh like outer membrane of the bacteria. It achieves this effect in a similar manner to the mechanism of Vancomycin. Vancomycin (and Telavancin) prevent the incorporation of NAM (N-acetylmuramic acid) and NAG (N-acetylglucosamine) subunits into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls. Secondly, Telavancin binds to the bacterial membrane and disrupts membrane barrier function.

Telavancin is a lipoglycopeptide antibiotic, and is semisythetic, being a derivative of the natural product Vancomycin, it has a molecular weight of 1755.6g.mol-1, as would be expected from a compound of this size, it comprehensively fails all the components of the Rule-of-Five. Telavancin is lipophillic and as expected, is not highly soluble in water. Following injection, Telavancin has a volume of distribution of 145mL/kg, a plasma half-life of 8hr and a clearance of 13.9mL/hr/kg.

Telavancin is available in the form of a reconstitutable powder for injection. Recommended dosage and full prescribing information can be found here. A course of treatment usually last seven or fourteen days and is a once daily dose of 10mg/kg (given as an hour long infusion). For a 'typical' adult of mass 70kg, this is a once daily dose of 700mg, this equates to a relatively large molar dosage (ca. 400umol).

Telavancin has a boxed warning.

Televancin has a complicated tricyclic structure, there are seven amino-acids as the core of the structure (the 'peptide' part of the lipoglycopeptide name), there are two sugar rings (the 'glyco' part of the name), and then, on the right hand part of the image above, a long lipophillic chain (the 'lipo' part of the lipoglycopeptide name). The biosynthesis of the parent natural product is fascinating, and is covered here. The specific differences of Telavancin compared to Vancomycin are the addition of the lipophillic alkyl chain, and the addition of the phosphate group (in the bottom right of the image). The glycopeptide antibiotic class of drugs include other Vancomycin derivatives, for example, Teicoplanin (launched as Targocid), Oritavancin (phase III trials), Dalbavancin (phase III trials) and the more chemically dissimilar Ramoplanin (phase III trials). 

<NAME="Telavancin" >
<SMILES="CCCCCCCCCCNCCNC1(CC(OC(C1O)C)OC2C(C(C(OC2OC3=C4C=C5C=C3OC6=C(C=C(C=C6)C(C(C(=O)NC(C(=O)NC5C(=O)NC7C8=CC(=C(C=C8)O)C9=C(C(=C(C=C9C(NC(=O)C(C(C1=CC(=C(O4)C=C1)Cl)O)NC7=O)C(=O)O)O)CNCP(=O)(O)O)O)CC(=O)N)NC(=O)C(CC(C)C)NC)O)Cl)CO)O)O)C">
<InChI="InChI=1S/C80H106Cl2N11O27P/c1-7-8-9-10-11-12-13-14-21-85-22-23-87-80(5)32-57(115-37(4)71(80)103)119-70-68(102)67(101)55(34-94)118-79(70)120-69-53-28-41-29-54(69)117-52-20-17-40(27-46(52)82)65(99)63-77(109)91-61(78(110)111)43-30-50(96)44(33-86-35-121(112,113)114)66(100)58(43)42-25-38(15-18-49(42)95)59(74(106)93-63)90-75(107)60(41)89-73(105)48(31-56(83)97)88-76(108)62(92-72(104)47(84-6)24-36(2)3)
64(98)39-16-19-51(116-53)45(81)26-39/h15-20,25-30,36-37,47-48,55,57,59-65,67-68,70-71,79,84-87,94-96,98-103H,7-14,21-24,31-35H2,16H3,(H2,83,97)(H,88,108)(H,89,105)(H,90,107)(H,91,109)(H,92,104)(H,93,106)(H,110,111)(H2,112,113,114)/t37-,47+,48-,55+,57-,59+,60+,61-,62+,63-,64+,65+,67+,68-,70+,71+,79-,80-/m0/s1" >
<InChIKey="ONUMZHGUFYIKPM-MXNFEBESSA-N" >
<ChemDraw=Telavancin.cdx >

The license holder is Theravance and www.vibativ.com is the product website.

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