Viral kinetic models have proven useful in characterizing treatment effectiveness during HCV therapy with interferon (IFN) as well as with direct-acting antivirals (DAAs).
Methods
Here we use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with setrobuvir, a non-nucleosidic inhibitor of the HCV NS5B polymerase enzyme. Using PK data from three studies in healthy volunteers and PK and VK data from a Phase I study, where setrobuvir was administered for 3 days, we fitted a two-compartment PK model with first-order absorption and lag-time, an Emax pharmacodynamics model and a standard biphasic VK model.
Results
Setrobuvir's EC50 and Hill coefficient and the viral clearance rate were significantly different (P=0.014, P<0.001 and P=0.004, respectively) between patients infected with HCV subtypes 1b and 1a, leading to an increased viral load decline in patients infected with genotype 1b virus.
Conclusions
Understanding the combined effects of PK/VK on the performance of a non-nucleoside polymerase inhibitor such as setrobuvir could provide valuable insights into their use in combination with other DAAs as well as to optimize future therapy. Further, our work suggests that patients infected with subtype 1a would need higher doses than those infected with subtype 1b to achieve the same effectiveness. Whether this is true for other non-nucleoside polymerase inhibitors needs to be examined.
References
1.
HoofnagleJ.H.Course and outcome of hepatitis C.Hepatology2002; 36 5 Suppl 1: s21–s29.
2.
Mohd HanafiahK., GroegerJ., FlaxmanA.D., WiersmaS.T.Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence.Hepatology2013; 57: 1333–1342.
3.
AbdelmalekM.F., FirpiR.J., Soldevila-PicoC.Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C.Liver Transpl2004; 10: 199–207.
4.
PearlmanB.L., TraubN.Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more.Clin Infect Dis2011; 52: 889–900.
5.
LawitzE., Rodriguez-TorresM., DeMiccoM.Antiviral activity of ANA598, a potent non-nucleoside polymerase inhibitor, in chronic hepatitis C patients.J Hepatol2009; 50: S384.
6.
JensenD.M., BrundaM., ElstonR.Interferon-free regimens containing setrobuvir for patients with genotype 1 chronic hepatitis C: a randomized, multicenter study.Liver Int2016; 36: 505–514.
7.
PerroneP., DaverioF., ValenteR.First example of phosphoramidate approach applied to a 4′-substituted purine nucleoside (4′-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus.J Med Chem2007; 50: 5463–5470.
8.
ReddyM.B., MorcosP.N., PogamS.L.Pharmacokinetic/ pharmacodynamic predictors of clinical potency for hepatitis C non-nucleoside polymerase and protease inhibitors.Antimicrob Agents Chemother2012; 56: 3144–3156.
9.
SnoeckE., ChanuP., LavielleM.A comprehensive hepatitis C viral kinetic model explaining cure.Clin Pharmacol Ther2010; 87: 706–713.
10.
NeumannA.U., LamN.P., DahariH.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy.Science1998; 282: 103–107.
11.
GuedjJ., DahariH., ShudoE., SmithP., PerelsonA.S.Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128).Hepatology2012; 55: 1030–1037.
12.
GuedjJ., DahariH., PohlR.T., FerenciP., PerelsonA.S.Understanding silibinin's modes of action against HCV using viral kinetic modeling.J Hepatol2012; 56: 1019–1024.
13.
GuedjJ., PerelsonA.S.Second-phase hepatitis C virus RNA decline during telaprevir-based therapy increases with drug effectiveness: implications for treatment duration.Hepatology2011; 53: 1801–1808.
14.
AdiwijayaB.S., KiefferT.L., HenshawJ.A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection.PLOS Comput Biol2012; 8: e1002339.
15.
AdiwijayaB.S., HerrmannE., HareB.A multi-variant, viral dynamic model of genotype 1 HCV to assess the in vivo evolution of protease-inhibitor resistant variants.PLOS Comput Biol2010; 6: e1000745.
16.
MallalieuN.L., RahimyM.H., CrowleyC.A., ApplemanJ.R., SmithP.F., FreddoJ.L.Pharmacokinetics and pharmacodynamics of setrobuvir, an orally administered hepatitis C virus non-nucleoside analogue inhibitor.Clin Ther2014; 36: 2047–2063.e3.
17.
GuedjJ., PangP.S., DenningJ.Analysis of the hepatitis C viral kinetics during administration of two nucleotide analogues: sofosbuvir (GS-7977) and GS-0938.Antivir Ther2014; 19: 211–220.
18.
CaniniL., ChatterjeeA., GuedjJ.A pharmacokinetic/ viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV.Antivir Ther2015; 20: 469–477.
19.
KuhnE., LavielleM.Maximum likelihood estimation in nonlinear mixed effects models.Comput Stat Data Anal2005; 49: 1020–1038.
20.
PinheiroJ.C., BatesD.M.Mixed-effects models in S and S-PLUS.New-York: Springer-Verlag2000.
21.
LaouénanC., GuedjJ., MentréF.. Clinical trial simulation to evaluate power to compare the antiviral effectiveness of two hepatitis C protease inhibitors using nonlinear mixed effect models: a viral kinetic approach.BMC Med Res Methodol2013; 13: 60.
22.
SchwarzG.Estimating the dimension of a model.Ann Stat1978; 6: 461–464.
23.
ToutainP.L., Bousquet-MélouA.Plasma terminal half-life.J Vet Pharmacol Ther2004; 27: 427–439.
24.
CaniniL., GuedjJ., ChatterjeeA., Lemenuel-DiotA., SmithP.F., PerelsonA.S.Modelling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection.Antivir Ther2016; 21: 297–306.
25.
DixitN.M., Layden-AlmerJ.E., LaydenT.J., PerelsonA.S.Modelling how ribavirin improves interferon response rates in hepatitis C virus infection.Nature2004; 432: 922–924.
26.
AdiwijayaB.S., HareB., CaronP.R.Rapid decrease of wild-type hepatitis C virus on telaprevir treatment.Antivir Ther2009; 14: 591–595.
27.
RongL., GuedjJ., DahariH.Analysis of hepatitis C virus decline during treatment with the protease inhibitor danoprevir using a multiscale model.PLOS Comput Biol2013; 9: e1002959.
28.
GuedjJ., DahariH., RongL.Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life.Proc Natl Acad Sci U S A2013; 110: 3991–3996.
29.
DahariH., CaniniL., GrawF.HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir.J Hepatol2016; 64: 1232–1239.
30.
PowersK.A., DixitN.M., RibeiroR.M., GoliaP., TalalA.H., PerelsonA.S.Modeling viral and drug kinetics: hepatitis C virus treatment with pegylated interferon alfa-2b.Semin Liver Dis2003; 23Suppl 2: 13–18.
31.
TalalA.H., RibeiroR.M., PowersK.A.Pharmacodynamics of PEG-IFN α differentiate HIV/ HCV coinfected sustained virological responders from nonresponders.Hepatology2006; 43: 943–953.
32.
DahariH., de AraujoE.S.A., HaagmansB.L.Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients: implications for treatment outcomes.J Hepatol2010; 53: 460–467.
33.
KirkovskyL., ZhouY., NorrisD.ANA598, a novel non-nucleoside inhibitor of HCVNS5B polymerase, exhibits favorable pharmacokinetic properties in multiple preclinical species.Hepatology2007; 46S1: 858A.
34.
SofiaM.J., ChangW., FurmanP.A., MosleyR.T., RossB.S.Nucleoside, nucleotide, and non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA-polymerase.J Med Chem2012; 55: 2481–2531.
