Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
Chen
Chih-Ming
CM
Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA.
He
Yupeng
Y
Lu
Liangjun
L
Lim
Hock Ben
HB
Tripathi
Rakesh L
RL
Middleton
Tim
T
Hernandez
Lisa E
LE
Beno
David W A
DW
Long
Michelle A
MA
Kati
Warren M
WM
Bosse
Todd D
TD
Larson
Daniel P
DP
Wagner
Rolf
R
Lanford
Robert E
RE
Kohlbrenner
William E
WE
Kempf
Dale J
DJ
Pilot-Matias
Tami J
TJ
Molla
Akhteruzzaman
A
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001581:Benzothiadiazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D003499:Cyclic S-Oxides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005838:Genotype; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy / Q000821:virology; D006801:Humans; D015394:Molecular Structure; D002679:Pan troglodytes; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D051381:Rats; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
C528231:A 837093; D000998:Antiviral Agents; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D012324:RNA-Dependent RNA Polymerase