The effect of hepatic impairment on the pharmacokinetics of asunaprevir, an HCV NS3 protease inhibitor.
BACKGROUND
It is necessary to evaluate the impact of hepatic impairment on the pharmacokinetic profile of direct-acting antiviral agents for the treatment of HCV infection.


METHODS
In this open-label, parallel group, multiple-dose study subjects (aged 18-70 years with a body mass index <35 kg/m(2)) with mild (n=6), moderate (n=6) and severe hepatic impairment (n=4) received asunaprevir 200 mg twice daily; healthy subjects (n=12) were matched (age, weight, gender) 1:1 to the first 4 subjects in each hepatic impairment group to act as controls. Pharmacokinetic sampling and analyses were performed on days 1 and 7 of dosing. Pharmacokinetic parameters were derived by non-compartmental methods. Geometric mean ratios (GMRs) and 90% CIs were used to assess the impact of hepatic impairment on the pharmacokinetics of asunaprevir, relative to healthy matched controls.


RESULTS
Compared with healthy subjects, mild hepatic impairment did not result in meaningful alterations in asunaprevir exposure (day 7 maximal plasma concentration [Cmax] GMR: 0.58 [90% CI 0.35, 0.98]; area under the plasma concentration-time curve in one dosing interval [AUCtau] GMR: 0.79 [90% CI 0.55, 1.15]); clinically significant increases in asunaprevir exposure were observed in subjects with moderate (Cmax GMR: 5.03 [90% CI 2.99, 8.47]; AUCtau GMR: 9.83 [90% CI 6.76, 14.28]) and severe hepatic impairment (Cmax GMR: 22.92 [90% CI 12.57, 41.81]; AUCtau GMR: 32.08 [90% CI 20.84, 49.40]). Correlation between increased asunaprevir exposure and all individual components of the Child-Pugh classification system was observed in subjects with moderate and severe hepatic impairment.


CONCLUSIONS
Mild hepatic impairment does not meaningfully affect the pharmacokinetic profile of asunaprevir. The dosing of asunaprevir in patients with moderate-to-severe hepatic impairment is not recommended. Clinicaltrials.gov identifier NCT01019070.
Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA. Timothy.Eley@bms.com.
Timothy
T
Eley
Bing
B
He
Ih
I
Chang
Elizabeth
E
Colston
Michael
M
Child
William
W
Bedford
Hamza
H
Kandoussi
Claudio
C
Pasquinelli
Thomas C
TC
Marbury
Richard J
RJ
Bertz
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D015992:Body Mass Index; D016022:Case-Control Studies; D004334:Drug Administration Schedule; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D007546:Isoquinolines; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C571889:asunaprevir