icon-folder.gif   Conference Reports for NATAP  
  49th ICAAC
San Francisco, CA
September 12-15, 2009
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Discovery of GS-9350: A Novel Pharmacoenhancer without Anti-HIV Activity
  Reported by Jules Levin
ICAAC Sept 12 2009 San Francisco
L Xu,1 H Liu,1 BP Murray,2 C Callebaut,3 A Hon,1 R Vivian,1 MS Lee,2 L Tsai,3 K Stray,3 G Eisenberg,2 J Chau,2 R Strickley,4 J Koziara,4 Y Choi,1 C Cannizzaro,5 S Swaminathan,5 GR Rhodes,2 and MC Desai1 Department of 1Medicinal Chemistry; 2Drug Metabolism; 3Biology; 4Formulation and 5Structural Chemistry, Gilead Sciences, Inc., Foster City, CA, USA


Ritonavir (RTV), an HIV protease inhibitor (PI), is also a potent mechanism-based inhibitor of human CYP3A. It is now mainly used as a pharmacoenhancer to improve pharmacokinetics of coadministered HIV PIs, which are primarily metabolized by CYP3A
Coadministeration of low dose ritonavir with HIV PIs has reduced pill burden and simplified regimens, and has served as a cornerstone of PI-based regimens - Ritonavir has been used for over 10 years in HIV-infected patients
Elvitegravir (EVG, GS-9137), an integrase inhibitor, can be dosed once-daily when boosted with ritonavir
Ritonavir has limitations when used as a CYP3A inhibitor
- Potent anti-HIV activity, may cause emergence of resistance when used at a low/subtherapeutic dose
- Poor aqueous solubility results in inconvenient dose form
- Requirement for refrigeration and challenging for co-formulation
- Associated with lipid disorders and GI-side effects
- Induction liability for off-target drug interactions (CYP, Pgp, UGT)
CYP inhibitors that can overcome these limitations were designed
The discovery, structure-activity relationships (SAR), pharmacokinetic profile, and synthesis of a novel series of CYP3A inhibitors are presented in this poster
In phase I, at 100 and 200 mg, once daily GS-9350 reduced the clearance of midazolam (a CYP3A substrate) by 90% and 95%, respectively
In phase I, GS-9350 (150 mg, once daily), when used as a component of integrase fi xed-dose regimen QUAD, enhanced the PK of elvitegravir to provide comparable Ctrough to that boosted with 100 mg once daily ritonavir
In phase I, GS-9350 (150 mg, once daily) enhanced the PK of atazanavir bioequivalent to that obtained when coadministered with 100 mg once daily ritonavir (see Poster A1-1301)
GS-9350 is being evaluated in Phase II studies in HIV-infected patients
















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