In this study, mathematical modeling of viral kinetics combined with pharmacokinetics was used to evaluate the pharmacodynamic properties of alb-IFN, a long-acting IFN being investigated for treatment of CHC at 2-week and 4-week dosing intervals. Thus, it is of importance to determine the viral dynamics and pharmacodynamics of alb-IFN during the prolonged dosing interval. A key factor in achieving a virologic response (> 2 log10 IU/mL) at Day 28 is the ability to rapidly achieve high (> 90%) antiviral effectiveness in blocking viral production and to maintain it throughout the dosing interval. The maximal antiviral quotient (MQ) and inhibitory quotient (IQ) quantify the blocking effectiveness at Day 4 (maximal drug concentration) and at the end of the dosing interval (trough concentration), respectively, relative to the EC90. Importantly, a low second-order sensitivity to declining drug levels (Nhill ~ 1) allows for maintaining blocking effectiveness > EC90 at the end of the dosing interval (IQ > 1). Finally, the loss rate of infected cells—a host factor that is related to the second-phase slope of viral decline5—also plays a role in achieving virologic response. Thus, the viral kinetic profile reflects the interplay of the pharmacokinetic properties of the drug with the host/viral factors, both in terms of sensitivity to the drug and the loss of infected cells.
In the present study of IFN-naïve patients with genotype 1 CHC, alb-IFN 900 µg and 1200 µg showed comparably high blocking effectiveness throughout the entire 14-day dosing interval in the majority of patients. In particular, 73%–77% of patients achieved blocking effectiveness > 90% (MQ > 1). In addition, an IQ > 1 was maintained in the majority of patients, reflecting a high MQ, extended drug t½, and low sensitivity (Nhill) to declining and trough concentrations of alb-IFN. Moreover, even in patients with an IQ << MQ, and especially when IQ was < 1 (where a viral rebound can occur), a low Nhill remained an important factor in dampening the rebound and preventing viremia from returning to baseline within the 2-week dosing interval.
It is interesting to note that although the first phase viral decline in the whole dosing range studied (including the lower doses of 200 µg, 450 µg, and 670 µg) showed a dose dependence,10 as previously observed for standard interferon-a,5 a significant difference was not observed between the 900 µg and 1200 µg doses in the viral kinetic (eg, first phase decline) or pharmacodynamical parameters (eg, MQ). In fact, there is a trend for a somewhat better response in the 900 µg group than the higher 1200 µg group (Figure 1B and Table 2). This may be either due to a statistical fluctuation in the distribution of more difficult-to-treat patients between the dose groups, due to the small numbers of patients in each group, or may be indicative of a more profound dynamical aspect related to mode of action of interferon-a. For example, one may hypothesize that very high doses of alb-IFN may lead to IFN-receptor saturation, causing cells to respond less well to IFN. This, in fact, may be related to the transient increase in HCV-RNA observed at Day 1–Day 7, with no parallel decline in alb-IFN levels at the same time, that are more frequently observed at the high-dose group. However, since no data on IFN-receptor levels or other indicators of host response to IFN are available in this study, it is not possible to further study this question here, and further prospective studies of this question are warranted.
The derivation of the normalized pharmacodynamic parameters MQ and IQ, which are dimensionless since Cmax and trough concentration are scaled by EC90 with the same drug units, could allow comparison of the pharmacodynamic profiles of different anti-HCV agents. Tallal et al14 demonstrated that the median quotient (comparable to MQ in the present study) and inhibitory quotient of pegylated IFN-a2b were predictive of sustained virologic response, which is consistent with the observation in this study that MQ and IQ with alb-IFN also were predictive of virologic response. However, since Tallal et al14 studied HIV/HCV–co-infected patients, and there are no other published studies estimating the pharmacodynamics parameters, it is not possible to compare the pharmacodynamic profile of pegylated IFN-a2b with that of alb-IFN in the present study of HCV–mono-infected patients.
The comparison of the viral kinetics parameters observed here with alb-IFN to those observed in studies of HCV kinetics during peg-IFN-a2a and peg-IFN-a2b15,16 therapy show a comparable second phase decline for all 3 drugs. However, alb-IFN and peg-IFN-a2b seem to show a somewhat greater first phase decline than peg-IFN-a2a. On the other hand, peg-IFN-a2b gives rise to significantly more transient rebounds at the end of each dosing period (1 week for peg-IFN and 2 weeks for alb-IFN) as compared to alb-IFN and peg-IFN-a2a. These results could indicate that alb-IFN exhibits a high MQ, similar to that of peg-IFN-a2b, as well as a high IQ, similar to that of peg-IFN-a2a. However, it must be noted that this comparison is based on results from different small studies and thus could be prone to statistical inaccuracy. Definitive comparisons of pharmacodynamic profiles of different antiviral drugs await randomized studies using accepted definitions for MQ and IQ.
Recent studies have shown that direct antiviral agents (eg, HCV protease or polymerase inhibitors) significantly improve early virologic response rates when used in combination with pegylated IFN and ribavirin.17–19 Although direct antiviral agents can block HCV replication to a great extent, there remains the potential for rapid evolution of resistant strains. Continuous and sufficiently high antiviral pressure of IFN-based treatment, when given in combination with direct antivirals, may reduce development of resistant mutations. Further, higher trough levels of pegylated IFNa-2a were recently shown to be important in reducing development of resistant mutations to telaprevir, an HCV protease inhibitor currently in development.20 It is, therefore, likely that IFNa with ribavirin will remain a critical component of therapeutic regimens for CHC in the foreseeable future.
The authors have used a combined mathematical model of frequent early measurement of pharmacokinetics and viral kinetics to estimate the pharmacodynamic parameters of alb-IFN therapy of HCV and to elucidate their importance in determining the successful response to treatment. The pharmacodynamic profile of alb-IFN, as demonstrated in this study, suggests its potential as a favorable IFN backbone for combination therapy with direct antiviral agents against HCV.
The authors thank Rachel S. Levy-Drummer for her contributions to this work. BioScience Communications, New York, New York, United States, provided editorial support.
- Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5(9):558–567.
- Patel K, Muir AJ, McHutchison JG. Diagnosis and treatment of chronic hepatitis C infection. BMJ. 2006;332(7548):1013–1017.
- Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975–982.
- Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358(9286):958–965.
- Neumann AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282(5386):103–107.
- Perelson AS, Herrmann E, Micol F, Zeuzem S. New kinetic models for the hepatitis C virus. Hepatology. 2005;42(4):749–754.
- Dahari H, Ribeiro RM, Perelson AS. Triphasic decline of hepatitis C virus RNA during antiviral therapy. Hepatology. 2007;46(1):16–21.
- Ferenci P, Fried MW, Shiffman ML, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol. 2005;43(3):425–433.
- Subramanian GM, Fiscella M, Lamousé-Smith A, Zeuzem S, McHutchison JG. Albinterferon alfa-2b: a genetic fusion protein for the treatment of chronic hepatitis C. Nat Biotechnol. 2007;25(12):1411–1419.
- Bain VG, Kaita KD, Yoshida EM, et al. A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol. 2006;44(4):671–678.
- Shudo E, Ribeiro RM, Perelson AS. Modelling hepatitis C virus kinetics during treatment with pegylated interferon alpha-2b: errors in the estimation of viral kinetic parameters. J Viral Hepat. 2008;15(5):357–362.
- Shudo E, Ribeiro RM, Perelson AS. Modelling the kinetics of hepatitis C virus RNA decline over 4 weeks of treatment with pegylated interferon alpha-2b. J Viral Hepat. 2008;15(5):379–382.
- Powers KA, Dixit NM, Ribeiro RM, Golia P, Talal AH, Perelson AS. Modeling viral and drug kinetics: hepatitis C virus treatment with pegylated interferon alfa-2b. Semin Liver Dis. 2003;23 Suppl 1:13–18.
- Talal AH, Ribeiro RM, Powers KA, et al. Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders. Hepatology. 2006;43(5):943–953.
- Hsu CS, Liu CJ, Lai MY, Chen PJ, Kao JH, Chen DS. Early viral kinetics during treatment of chronic hepatitis C virus infection with pegylated interferon alpha plus ribavirin in Taiwan. Intervirology. 2007;50(4):310–315.
- Silva M, Poo J, Wagner F, et al. A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE). J Hepatol. 2006;45(2):204–213.
- Lalezari J, Gane E, Rodriguez-Torres M, et al. Potent antiviral activity of the HCV nucleoside polymerase inhibitor R7128 with PEG-IFN and ribavirin: interim results of R7128 500mg bid for 28 days. Presented at the 43rd Annual Meeting of the European Association for the Study of the Liver in Milan, Italy, April 23–27, 2008.
- Forestier N, Reesink HW, Weegink CJ, et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology. 2007;46(3):640–648.
- Lawitz E, Rodriguez-Torres M, Muir AJ, et al. Antiviral effects and safety of telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in hepatitis C patients. J Hepatol. Epub 2008 Apr 29.
- Jacobson IM, Everson GT, Gordon SC, et al. Interim analysis results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis. Hepatology. 2007;46:315A.