Physicochemical properties of the nucleoside prodrug R1626 leading to high oral bioavailability.
The nucleoside analog R1479 is a potent and highly selective inhibitor of NS5b-directed hepatitis C virus (HCV) RNA polymerase in vitro. Because of its limited permeability, lipophilic prodrugs of R1479 were screened. Selection of the prodrug involved optimization of solubility, permeability, and stability parameters. R1626 has dissociation constant, intrinsic solubility, log partition coefficient (n-octanol water), and Caco-2 permeability of 3.62, 0.19 mg/mL, 2.45, and 14.95 x 10(-6) cm/s, respectively. The hydrolysis of the prodrug is significantly faster in the Caco-2 experiments than in hydrolytic experiments, suggesting that the hydrolysis is catalyzed by enzymes in the cellular membrane. Using GastroPlus, the physical properties of R1626 successfully predict the dose dependence of the pharmacokinetics in humans previously studied. The program predicts that if the particle size of R1626 is less than 25 microm, it will be well absorbed. Prodrugs with a solubility of greater than 100 microg/mL and permeability in the Caco-2 assay greater than 3 x 10(-6) cm/s are expected to achieve a high fraction absorbed.
Brandl
Michael
M
Roche Palo Alto, LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. michael.brandl@roche.com
Wu
Xiaoyang
X
Holper
Marites
M
Hong
Lei
L
Jia
Zhongjiang
Z
Birudaraj
Raj
R
Reddy
Micaela
M
Alfredson
Tom
T
Tran
Tony
T
Larrabee
Susan
S
Hadig
Xu
X
Sarma
Keshab
K
Washington
Carla
C
Hill
George
G
Smith
David B
DB
D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D003562:Cytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D009705:Nucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010316:Particle Size; D010539:Permeability; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D003562:Cytidine; D012321:DNA-Directed RNA Polymerases; D009705:Nucleosides; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C508950:4'-azidocytidine; C530825:balapiravir