Pharmacokinetic enhancement of the hepatitis C virus protease inhibitors VX-950 and SCH 503034 by co-dosing with ritonavir.
Inhibitors of hepatitis C virus (HCV) protease have shown marked antiviral activity in short-term clinical studies in HCV-infected individuals. The interaction of the investigational HCV protease inhibitors VX-950 and SCH 503034 with ritonavir, a potent inhibitor of cytochrome P450 3A, was studied in vitro and in vivo. In rat and human liver microsomes, the metabolism of VX-950 and SCH 503034 was strongly inhibited by the presence of 4 microM ritonavir. Upon co-dosing either VX-950 or SCH 503034 with ritonavir in rats, plasma exposure of the HCV protease inhibitors was increased by > 15-fold, and plasma concentrations 8 h after dosing were increased by > 50-fold. A human pharmacokinetic model of VX-950 co-administered with low-dose ritonavir suggested that improved efficacy and/or dosing convenience may be feasible by pharmacokinetic enhancement with ritonavir.
Kempf
Dale J
DJ
Global Pharmaceutical Research & Development Division Abbott, Abbott Park, IL, USA. dale.kempf@abbott.com
Klein
Cheri
C
Chen
Hui-Ju
HJ
Klein
Larry L
LL
Yeung
Clinton
C
Randolph
John T
JT
Lau
Yau Y
YY
Chovan
Linda E
LE
Guan
Zhiwen
Z
Hernandez
Lisa
L
Turner
Teresa M
TM
Dandliker
Peter J
PJ
Marsh
Kennan C
KC
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*
D000998:Antiviral Agents; D009842:Oligopeptides; D011480:Protease Inhibitors; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D019438:Ritonavir