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PL-100, a Next Generation Protease Inhibitor Against Drug-Resistant HIV: In Vitro and In Vivo Metabolism
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IDSA, Toronto, Oct 2006
J. J. WU, B. STRANIX, G. MILOT, M. GE, S. DANDACHE, C. PANCHAL;
Ambrilia Biopharma Inc, Verdun, Canada.
Background: PL-100 is a novel HIV-1 protease inhibitor (PI) with a favorable cross-resistance profile and high genetic 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 live microsomes was carried out according to standard methods. In induction studies, freshly isolated human primary hepatocytes were incubated with PL-100 for 48 h at final concentrations of 0.5, 5 or 25 µM. Activity of CYP2C9 and CYP3A4 was assayed according 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, nelfinavir and ritonavir. PL-100 was more stable than lopinavir, saquinavir, indinavir. Metabolism of PL-100 in human liver microsomes was significantly inhibited by ritonavir, which was consistent with in vivo data 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 CYP3A4 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 might be both substrate and inhibitor of CYP3A4. Pro-drug PPL-100, with significantly improved aqueous solubility and oral bioavailability, is a promising drug for the treatment of PI-naïve and experienced patients.
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