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PL-100, a Next Generation Protease Inhibitor Against Drug-Resistant HIV:
In vitro & IN Vivo Metabolism
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Reported by Jules Levin
46th ICAAC
San Francisco, Sept 27-30, 2006
Authors: Jinzi J. Wu, Brent R. Stranix, Guy Milot, Michael Ge, Serge Dandache, Andre Forte, Isaebelle Pelletier, Anick Dubois, Odette Belanger and Chandra Panchal. Ambrilia Biopharma Inc, Montreal, Canada
Author Conclusions:
- Pl-100 is predominatly metabolized by CYP3A4
- PL-100 does not induce activities of CYP3A4 and 2C9
- PL-100 is an inhibitor of CYP3A4/5 and PPL-100 is a safe, long-lasting PK
enhancer of marketed PIs
- PPL-100, a prodrug of PL-100, has the potential to be a once-daily, un-boosted PI.
ABSTRACT
Background: PL-100 is a novel HIV-1 protease inhibitor (PI) with a favorable cross-resistance profile and high generic barrier. We have developed a phosphorylated pro-drug of PL-100, namely PPL-100 which is currently in Phase I human clinical trials.
Methods: In vitro metabolism of PL-100 in human and rat liver microsomes was carried out according to standard methods. In induction studies, freshly isolated human primary hepatocytes were incubated with PL-100 for 48 hours at final concentrations of 0.5, 5 or 25 uM. Activity of CYO2C9 and CYP3A4 was assayed accordingf to standard methods. In vivo metabolism and pharmacokinetics were carried out in normal and portal vein-cannulated rats. PL-100 or PPL-100 was orally dosed. Plasma samples were analyzed by LC-MS.
Results: In vitro metabolism of PL-100 in human and rat liver microsomes was compared with amprenavir, lopinavir, saquinavir, indinavir. Metabolism of PL-100 in human liver microsomes was significantly inhibited by ritonavir, which was consistent with in vivo data showing that pharmacokinetics of this PI was significantly boosted by ritonavir. PL-100 did not inhibit CYP2C9 and CYP2D6 but did inhibit CYP3A4 in vitro. PL-100 did not induce the activity of CYP2C9 and CYP 3A4 in the freshly isolated primary human hepatocytes. Pro-drug PPL-100 was found to be >1000-fold more water soluble than PL-100 and had shown 2- to 3-fold improvement over PL-100 in key pharmacokinetic parameters in rats. The studies in cannulated rats demonstrate that PL-100 was the major metabolite found in the portal vein and systemic circulation when pro-drug PPL-100 was orally dosed.
Conclusions: Our data suggest that PL-100 is both a substrate and an inhibitor of CYP3A4. Prodrug PPL-100, with significantly improved aqueous solubility and oral bioavailability, is a promising drug for the treatment of PI-naïve and experienced HIV/AIDS patients.
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