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/m2) 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.
References
1.
Wartelle-BladouC., Le FolgocG., BourliereM., LecomteL.Hepatitis C therapy in non-genotype 1 patients: the near future.J Viral Hepat2012; 19: 525–536.
2.
PoordadF., DieterichD.Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents.J Viral Hepat2012; 19: 449–464.
3.
McPheeF., SheafferA.K., FriborgJ.Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032).Antimicrob Agents Chemother2012; 56: 5387–5396.
4.
SuzukiY., IkedaK., SuzukiF.Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options.J Hepatol2013; 58: 655–662.
5.
LokA.S., GardinerD., HezodeC.Sustained virologic response in chronic HCV genotype (GT) 1-infected null responders with combination of daclatasvir (DCV; NS5A inhibitor) and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV).Hepatology2012; 56Suppl 4: 230A.
6.
BronowickiJ.P., PolS., ThuluvathP.J.Randomized study of asunaprevir plus peginterferon alfa and ribavirin for previously untreated genotype 1 chronic hepatitis C.Antivir Ther2013; 18: 885–893.
7.
EleyT., PasquinelliC., WendelburgP.Safety and pharmacokinetics of BMS-650032 following multiple ascending doses for 14 days in healthy subjects.50th Interscience Conference Antimicrobial Agents Chemotherapy. 12–15 September 2010, Boston, MA, USA. Abstract A1-1995.
8.
KalliokoskiA., NiemiM.Impact of OATP transporters on pharmacokinetics.Br J Pharmacol2009; 158: 693–705.
9.
EleyT., HanY.H., HuangS.P.In vivo and in vitro assessment of asunaprevir (BMS-650032) as an inhibitor and substrate of organic anion polypeptide (OATP) trasporters in healthy volunteers.Rev Antivir Ther Infect Dis2012; 6: 7.
10.
PasquinelliC., McPheeF., EleyT.Single and multiple ascending dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C.Antimicrob Agents Chemother2012; 56: 1838–1844.
11.
BronowickiJ-P, PolS., ThuluvathP.Asunaprevir (ASV; BMS-650032), an NS3 protease inhibitor, in combination with peginterferon and ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C infection.J Hepatol2012; 56Suppl 2: S431–S432.
12.
BronowickiJ., RatziuV., GadanoA.Asunaprevir with peginterferon-alfa and ribavirin in treatment-naive patients with genotype-1 or -4 chronic hepatitis C: SVR24 results from a randomized phase 2B study (AI447016).J Hepatol2013; 58Suppl 1: S571–S572.
13.
EleyT., ChanP., SverdlovO.Improved bioavailability and mitigated food effect for asunaprevir utilizing a lipid-based formulation: similar exposure with 100 mg twice daily softgel capsule relative to 200 mg twice daily of Phase 2 tablet.52nd Interscience Conference Antimicrobial Agents Chemotherapy. 9–12 September 2012, San Francisco, CA, USA. Abstract/Poster A-1247.
14.
EleyT., HeB., HuangS.Pharmacokinetics of the NS3 protease inhibitor, asunaprevir (ASV, BMS-650032), in Phase I studies in subjects with or without chronic hepatitis C.Clinical Pharm in Drug Dev2013; 2: 316–327.
15.
EleyT., HeB., HuangS.Effect of multiple-dose ketoconazole and the effect of multiple-dose rifampin on the pharamcokinetics (PK) of the NS3 protease inhibitor asunaprevir.Rev Antivir Ther Infect Dis2013; 6: 15.
