Pharmacokinetic and pharmacodynamic modeling of pegylated-interferon alfa
Authors: Rositsa B. Dimova, Andrew H. Talal
Journal: Journal of Hepatology (2010)

Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients: Implications for treatment outcomesJournal of HepatologyVol. 53Issue 3PreviewThe pharmacokinetics and pharmacodynamics of pegylated-interferon-α-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Full-Text PDF Hepatitis C virus (HCV) infection affects approximately 170 million individuals worldwide [1Shepard C.W. Finelli L. Alter M.J. Global epidemiology of hepatitis C virus infection.Lancet Infect Dis. 2005; 5: 558-567Abstract Full Text Full Text PDF PubMed Scopus (2281) Google Scholar, 2Davis G.L. Keeffe E.B. Balart L.A. Advances in liver disease: highlights from the 56th Annual Meeting of the American Association for the Study of Liver Disease.Rev Gastroenterol Disord. 2006; 6: 48-61Google Scholar]. Among those exposed to HCV, between 50% and 80% develop chronic infection that may result in progressive liver fibrosis and consequently in cirrhosis and/or hepatocellular carcinoma. Among HIV-infected people, approximately 15–30% are co-infected with HCV, and the hepatitis virus is a leading cause of death in these individuals [3Kadam J.S. Talal A.H. Changing treatment paradigms: hepatitis C virus in HIV-infected patients.AIDS Patient Care STDS. 2007; 21: 154-168Crossref PubMed Scopus (11) Google Scholar, 4Gonzalez S.A. Talal A.H. Hepatitis C virus in human immunodeficiency virus-infected individuals: an emerging comorbidity with significant implications.Semin Liver Dis. 2003; 23: 149-166Crossref PubMed Scopus (30) Google Scholar]. Unfortunately, therapeutic efficacy is diminished in HIV/HCV co-infected compared to HCV mono-infected patients to current standard therapy, which consists of pegylated-interferon (PEG-IFN) and ribavirin (RBV) [[3]Kadam J.S. Talal A.H. Changing treatment paradigms: hepatitis C virus in HIV-infected patients.AIDS Patient Care STDS. 2007; 21: 154-168Crossref PubMed Scopus (11) Google Scholar]. Two separate formulations of PEG-IFN have been approved, alfa-2a and alfa-2b, each with different pharmacokinetic profiles [[5]Foster G.R. Pegylated interferons for the treatment of chronic hepatitis C: pharmacological and clinical differences between peginterferon-alpha-2a and peginterferon-alpha-2b.Drugs. 2010; 70: 147-165Crossref PubMed Scopus (96) Google Scholar], and these medications are typically administered for 48 weeks. They can be difficult to tolerate; consequently, therapy in those unlikely to respond should be limited. According to current guidelines, patients should be treated for at least 12 weeks to determine whether a 2-log HCV RNA decline has occurred, thereby justifying treatment continuation [[6]Ghany M.G. Strader D.B. Thomas D.L. Seeff L.B. Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (2644) Google Scholar]. However, the identification of parameters that could be used earlier for therapeutic intervention would be of tremendous importance. Successful treatment outcome for HCV in PEG-IFN/RBV treated patients has been defined as undetectable HCV RNA in serum 6 months after the end of treatment (sustained virological response [SVR]). Nonresponders (NR) are those in whom serum HCV RNA is detectable 6 months post treatment cessation. SVR occurs in 27–40% of HIV/HCV coinfected treated patients [[3]Kadam J.S. Talal A.H. Changing treatment paradigms: hepatitis C virus in HIV-infected patients.AIDS Patient Care STDS. 2007; 21: 154-168Crossref PubMed Scopus (11) Google Scholar]. Mathematical modeling of HCV RNA decay has been used to assess the effectiveness of anti-HCV treatment [7Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. et al.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1911) Google Scholar, 8Talal A.H. Shata M.T. Markatou M. Dorante G. Chadburn A. Koch R. et al.Virus dynamics and immune responses during treatment in patients coinfected with hepatitis C and HIV.J Acquir Immune Defic Syndr. 2004; 35: 103-113Crossref PubMed Scopus (26) Google Scholar]. Early viral dynamic models that used standard IFN alfa assumed constant effectiveness, which was appropriate when IFN was administered thrice weekly. In contrast, when patients were treated with PEG-IFN alfa-2b, time-varying IFN concentration was observed [[9]Glue P. Fang J.W. Rouzier-Panis R. Raffanel C. Sabo R. Gupta S.K. et al.Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data.Clin Pharmacol Ther. 2000; 68: 556-567Crossref PubMed Scopus (487) Google Scholar]. To account for these changes, Powers et al. incorporated pharmacokinetic/pharmacodynamic parameters into a viral dynamic model [[10]Powers K.A. Dixit N.M. Ribeiro R.M. Golia P. Talal A.H. Perelson A.S. Modeling viral and drug kinetics: hepatitis C virus treatment with pegylated interferon alfa-2b.Semin Liver Dis. 2003; 23: 13-18PubMed Google Scholar]. Pharmacokinetics (PK) establishes the connection between drug inflow and concentration in blood and includes parameters such as drug absorption, elimination, and blood volume. Pharmacodynamics (PD) establishes the connection between drug concentration and clinical outcome. PK/PD of PEG-IFN/RBV has been modeled through partial differential equations constructed to explain the drug’s mechanism of action [[11]Dahari H. Shudo E. Ribeiro R.M. Perelson A.S. Mathematical modeling of HCV infection and treatment.Methods Mol Biol. 2009; 510: 439-453Crossref PubMed Google Scholar]. Using mechanistic models, one can estimate in vivo parameters that are not directly measurable, such as how effective a drug (i.e., IFN) is in blocking virus production, or to make inferences about other clinically-useful variables, such as the duration of treatment necessary to eradicate the virus [12Bonate P.L. Pharmacokinetic–pharmacodynamic modeling and simulation. Springer, New York, NY2006Google Scholar, 13Shudo E. Ribeiro R.M. Perelson A.S. Modeling HCV kinetics under therapy using PK and PD information.Expert Opin Drug Metab Toxicol. 2009; 5: 321-332Crossref PubMed Scopus (29) Google Scholar]. Limitations of the mechanistic models include difficulty in model validation as well as computational issues that may arise due to the approximating and iterative nature of the algorithms used to estimate the parameters and their convergence. An important question is whether PK/PD properties of PEG-IFN/RBV can identify HCV-infected patients early in treatment who are unlikely to respond. To address this issue, we constructed a dynamic model that incorporates PK/PD parameters and applied it to data obtained from 24 HIV/HCV co-infected patients treated with PEG-IFN alfa-2b/RBV [[14]Talal A.H. Ribeiro R.M. Powers K.A. Grace M. Cullen C. Hussain M. et al.Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders.Hepatology. 2006; 43: 943-953Crossref PubMed Scopus (71) Google Scholar]. We found that EC50, the median individual effective concentration of PEG-IFN, was significantly lower in SVR compared with NR patients. Additionally, the estimated PK parameters did not differ significantly between the two patient groups. Recent studies also evaluated the utility of PK/PD parameters for their ability to identify NR patients early in therapy [15Rozenberg L. Haagmans B.L. Neumann A.U. Chen G. McLaughlin M. Levy-Drummer R.S. et al.Therapeutic response to peg-IFN-alpha-2b and ribavirin in HIV/HCV co-infected African-American and Caucasian patients as a function of HCV viral kinetics and interferon pharmacodynamics.AIDS. 2009; 23: 2439-2450Crossref PubMed Scopus (18) Google Scholar, 16Asahina Y. Izumi N. Umeda N. Hosokawa T. Ueda K. Doi F. et al.Pharmacokinetics and enhanced PKR response in patients with chronic hepatitis C treated with pegylated interferon alpha-2b and ribavirin.J Viral Hepat. 2007; 14: 396-403Crossref PubMed Scopus (20) Google Scholar, 17Nicot F. Legrand-Abravanel F. Lafont T. Dubois M. Saune K. Pasquier C. et al.Serum concentrations of ribavirin and pegylated interferon and viral responses in patients infected with HIV and HCV.J Med Virol. 2008; 80: 1523-1529Crossref PubMed Scopus (34) Google Scholar]. Rozenberg et al. evaluated PK/PD and viral parameters and their association with treatment outcome in 23 HIV/HCV co-infected patients treated with PEG-IFN alfa-2b. These investigators additionally studied whether PK/PD parameters differ between African Americans and Caucasians and found that the EC50 was significantly lower in Caucasians. Moreover, patients who achieved an SVR maintained serum concentrations of IFN above the EC90, an improved estimator of antiviral sensitivity than EC50, for longer periods of time than NR patients. In comparison to the above-referenced studies that investigated PK/PD properties of PEG-IFN alfa-2b in co-infected patients [14Talal A.H. Ribeiro R.M. Powers K.A. Grace M. Cullen C. Hussain M. et al.Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders.Hepatology. 2006; 43: 943-953Crossref PubMed Scopus (71) Google Scholar, 15Rozenberg L. Haagmans B.L. Neumann A.U. Chen G. McLaughlin M. Levy-Drummer R.S. et al.Therapeutic response to peg-IFN-alpha-2b and ribavirin in HIV/HCV co-infected African-American and Caucasian patients as a function of HCV viral kinetics and interferon pharmacodynamics.AIDS. 2009; 23: 2439-2450Crossref PubMed Scopus (18) Google Scholar], in the current issue of the Journal of Hepatology, Dahari et al. performed a comprehensive analysis of PK/PD of PEG-IFN alfa-2a in 26 co-infected patients [[18]Dahari H. Affonso de Araujo E.S. Haagmans B.L. Layden T.J. Cotler S.J. Barone A.A. et al.Pharmacodynamics of PEG-IFN alpha-2a in HIV/HCV co-infected patients: Implications for treatment outcomes.J Hepatol. 2010; 53: 460-467Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. This analysis is particularly important because of the differences in pharmacokinetics between the two PEG-IFN preparations and, in addition, their decreased therapeutic efficacy in co-infected patients. Dahari et al. used mathematical models together with two-stage, individual-based, nonlinear least squares method to estimate the PK/PD parameters associated with PEG-IFN. Their main purpose was to discover PK/PD-related parameters that could be used to identify potential NR patients. PEG-IFN concentration and HCV RNA levels were sampled frequently until week 12. Five of the 26 patients were excluded from the modeling due to early treatment discontinuation. The authors estimated the PK parameters for the first week and for the twelfth week of treatment. They also estimated the maximum PEG-IFN effectiveness during the first dose, ε7max, and the infected cell loss rate, δ, for each patient. Then, they used nonparametric statistical methods to compare the estimated quantities between SVR and NR, between HCV genotypes 1 and 3, and between African Americans and Caucasians. The authors identified and described four viral kinetic patterns. In patients with a triphasic HCV RNA decay pattern, they fit the combined-PD model that includes additional terms for hepatocyte proliferation. In patients with a biphasic decline, they fit the combined biphasic-PD model. Based on their results, Dahari et al. conclude that none of the PK parameters can significantly differentiate between NR and SVR. However, they identified two PD parameters with 100% positive predictive value for the identification of SVR patients: (1) the maximum PEG-IFN effectiveness during the first dose, ε7max, and (2) the infected cell loss rate, δ. When comparing the PK/PD parameters between individuals infected with HCV genotypes 1 and 3; these authors concluded that EC50 is significantly lower, and that δ is significantly increased in genotype 3-infected individuals. In addition, they did not identify significant differences in the viral kinetic and pharmacodynamic parameters between Caucasians and African Americans. An important issue is the statistical technique used in the analysis of PK/PD data. In general, two statistical approaches, the two-stage nonlinear least squares approach (individual PK), and the nonlinear mixed effects model (population PK) (Table 1) have been established for the analysis of PK/PD data. Briefly, the two-stage (individual PK) approach requires that a large number of observations are obtained for each patient at the same time points in order to obtain parameter estimates. The first stage of this procedure consists of using nonlinear regression (nonlinear least squares) to estimate the PK/PD parameters for each individual separately. In the second stage, these parameters are summarized through computation of descriptive statistics (means, variances), and a subsequent analysis of dependencies between the estimated parameters and patient-related covariates can be performed. The three studies discussed above [14Talal A.H. Ribeiro R.M. Powers K.A. Grace M. Cullen C. Hussain M. et al.Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders.Hepatology. 2006; 43: 943-953Crossref PubMed Scopus (71) Google Scholar, 15Rozenberg L. Haagmans B.L. Neumann A.U. Chen G. McLaughlin M. Levy-Drummer R.S. et al.Therapeutic response to peg-IFN-alpha-2b and ribavirin in HIV/HCV co-infected African-American and Caucasian patients as a function of HCV viral kinetics and interferon pharmacodynamics.AIDS. 2009; 23: 2439-2450Crossref PubMed Scopus (18) Google Scholar, 18Dahari H. Affonso de Araujo E.S. Haagmans B.L. Layden T.J. Cotler S.J. Barone A.A. et al.Pharmacodynamics of PEG-IFN alpha-2a in HIV/HCV co-infected patients: Implications for treatment outcomes.J Hepatol. 2010; 53: 460-467Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] used this statistical technique. An alternative approach for analysis of PK/PD data is based on the nonlinear mixed effects models. This method is especially appropriate in sparse or unbalanced data situations (i.e., patients may have different sampling times or may have missed some measurements) and when the investigator is interested in making generalizations about the population from which the study subjects were randomly selected. In contrast to the two-stage approach, in this procedure the population parameters are estimated directly, and inter and intra-subject variability is incorporated into the model. As the presence of missing values is a common problem in studies of HCV-infected persons because of poor compliance among some HCV-infected populations, the population PK approach may be a useful tool for analyzing such data. The US Food and Drug Administration has issued guidelines concerning the use of population PK in the process of drug development [[19]Food and Drug Administration. Guidance for industry: population pharmacokinetics. Rockville, MD: US Department of Health and Human Services; 1999.Google Scholar].Table 1Summary of the characteristics of the population (nonlinear mixed effects model) pharmacokinetics and the individual two-stage (nonlinear least squares method) pharmacokinetic approach.Individual Two-Stage PharmacokineticsPopulation PharmacokineticsFocus on individualFocus on populationTools: nonlinear regression model based upon nonlinear least squares methodTools: nonlinear mixed effects modelData from each individual are modeled separatelyData from all individuals are modeled simultaneouslyNeeds rich data for each subjectHandles dense, sparse, and unbalanced data (even one observation per subject)Accounts for the different sources of variability (between-subject, within-subject)Important factors such as demographic, environmental, pathophysiological, etc., which explain subject variability, can be identifiedCan be used also for individualized inference Open table in a new tab In conclusion, identifying PK/PD models that describe the relationship between the concentration of the drug in the blood, the dose of the drug, other PK parameters and covariates is a very important aspect in the area of HCV therapeutics. Besides IFN, exploring differences in RBV pharmacokinetics, as has been done in various studies [17Nicot F. Legrand-Abravanel F. Lafont T. Dubois M. Saune K. Pasquier C. et al.Serum concentrations of ribavirin and pegylated interferon and viral responses in patients infected with HIV and HCV.J Med Virol. 2008; 80: 1523-1529Crossref PubMed Scopus (34) Google Scholar, 20Dahari H. Markatou M. Zeremski M. Haller I. Ribeiro R.M. Licholai T. et al.Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin.J Hepatol. 2007; 47: 23-30Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar], and the PK/PD of directly acting antivirals, are additional considerations that may differentiate SVR and NR patients. Explaining inter and intra-subject variability in the PK of a drug, or in viral kinetics, is a central goal of the analysis of PK/PD parameters. Studies investigating the mechanism of action of IFN performed to date have not identified PK parameters that significantly differ between SVR and NR patients. In contrast, some PD parameters have been identified with the ability to differentiate between these two patient groups. Dahari et al. investigated the important problem of modeling the pharmacokinetics of PEG-IFN alfa-2a and the HCV viral kinetics in HIV/HCV co-infected patients, which is motivated by the widespread use of PEG-IFN alfa-2a in clinical practice. The investigators found that the maximum PEG-IFN effectiveness during the first dose, and the infected cell loss rate can differentiate SVR from NR patients. Further research is needed to confirm the findings concerning the use of viral kinetic parameters as prognostic tools of treatment outcome and to determine their role in patient management. Dr. Andrew Talal has received research support from Schering Plough (presently Merck) and Merck, and research support and is on the speaker’s bureau of Genentech, a member of the Roche group.