Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Antiviral Therapy 10:201–205 Fast track Area-under-the-curve for peginterferon alpha-2a and peginterferon alpha-2b is not related to body weight in treatment-naive patients with chronic hepatitis C Raffaele Bruno*, Paolo Sacchi, Laura Maiocchi, Cristina Zocchetti, Valentina Ciappina, Savino Patruno and Gaetano Filice Division of Infectious and Tropical Diseases, IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy *Corresponding author: Tel: +39 0382 501080; Fax: +39 0382 529730; E-mail: [email protected] One reason for dosing a drug by body weight is to reduce interpatient variability in clinical response. This study evaluated the relationship between body weight and drug exposure for peginterferon alpha-2a and peginterferon alpha-2b used in combination with ribavirin for treating patients with chronic hepatitis C. These two products are dosed differently: peginterferon alpha-2a is flat-dosed at 180 µg regardless of body weight, whereas peginterferon alpha-2b is dosed by body weight at 0.5–1.5 µg/kg. Bodyweight dosing of peginterferon alpha-2b is purported to overcome the adverse effect of increased body weight on sustained virological response. To test this hypothesis, we measured the area-under-the-curve (AUC) for both drugs as part of a previously reported pharmacokinetics study. In total, 22 interferon-naive patients with chronic hepatitis C were treated for 12 weeks. Patients were randomly assigned in a 1:1 ratio to receive once-weekly peginterferon alpha-2a 180 µg (n=10) or peginterferon alpha-2b 1.0 µg/kg (n=12). Ribavirin was dosed by body weight at 1000 mg/day (≤75 kg) or 1200 mg/day (>75 kg). We found no correlation between body weight and AUC for either peginterferon alpha-2a or peginterferon alpha-2b. Considerable interpatient variability in AUC occurred for peginterferon alpha-2a [coefficient of variation (CV): 37.5%] and, despite dosing by body weight, for peginterferon alpha-2b (CV: 36.8%). Thus, there appears to be no rationale for a body-weight dosing regimen for peginterferon alpha-2a, and such dosing does not achieve more consistent AUC measurements in patients receiving peginterferon alpha-2b. Introduction Although body weight or body surface area may affect the pharmacokinetic characteristics of a drug, dosing of drugs based on body weight or body surface area in adults is largely restricted to chemotherapeutic agents, anaesthetics and heparin [1]. For many drugs, variations in pharmacokinetic properties related to body weight and body surface area are not sufficiently clinically significant to warrant dosing based on body weight [2]. Current therapy for chronic hepatitis C in treatmentnaive patients consists of combination therapy with peginterferon alpha and ribavirin [3–6]. The two commercially available peginterferon alpha products, peginterferon alpha-2a and peginterferon alpha-2b, differ significantly in their pharmacokinetic properties [1,7]. Peginterferon alpha-2a is flat-dosed at 180 µg per week [8], whereas peginterferon alpha-2b is dosed © 2005 International Medical Press 1359-6535 based on body weight at, specifically, 1.0–1.5 µg/kg per week [9]. These dosing regimens are derived from initial observations of the pharmacokinetics of the two molecular entities, demonstrating that, for peginterferon alpha-2a, body weight did not account for significant interpatient variability in drug distribution or clearance [1]. In contrast, body weight did have a small but statistically significant effect on the apparent drug clearance of peginterferon alpha-2b [10]. To determine the relationship between body weight and drug exposure for peginterferon alpha-2a (40 kD) and peginterferon alpha-2b (12 kD), we measured the area-under-the-curve (AUC) for both drugs as part of a previously reported study [7]. This study compared the effects of the drugs’ pharmacokinetics on the viral dynamics of the hepatitis C virus (HCV) over a 201 R Bruno et al. 12-week treatment period in interferon-naive patients with chronic hepatitis C. Patients and methods Patients The details of the clinical study protocol have been reported previously [7]. In brief, the study was conducted at the IRCCS San Matteo Hospital, Division of Infectious and Tropical Diseases, University of Pavia, Pavia, Italy. The study population consisted of 22 adult patients infected with HCV, all of whom were interferon-naive. Criteria for eligibility included serum HCV RNA levels ≥ 2000 copies/ml, serum alanine aminotransferase (ALT) values above the upper limit of normal and a liver biopsy result consistent with the diagnosis of chronic hepatitis C. Patients with HIV coinfection or decompensated liver disease were excluded. The study was approved by the Ethics Committee according to the Declaration of Helsinki and all patients gave written informed consent. Study design Patients were randomly assigned in a 1:1 ratio to receive either 180 µg peginterferon alpha-2a once weekly (PEGASYS®; Hoffmann-LaRoche, Basel, Switzerland) (n=10) or 1.0 µg/kg peginterferon alpha2b once weekly (PegIntron®; Schering-Plough, Kenilworth, NJ, USA) (n=12). Both drugs were administered by subcutaneous injection. Ribavirin was given orally at a dose of 1000 mg/day for patients weighing ≤ 75 kg and at 1200 mg/day for those weighing >75 kg. Pharmacokinetic analysis Area-under-the-curve (µg⋅h⋅ml–1) was calculated using the Kinetica™ software package, release 4.0 (Innaphase Corp, Philadelphia, PA, USA). Serum concentrations of both peginterferons were measured at baseline and at 24, 48, 120 and 168 h after administration by a quantitative sandwich enzyme-linked immunosorbent assay (ELISA) method developed at MDS Laboratories (Wangen, Switzerland). The details of the assay procedures have been previously described [7]. All calibration standards, the quality control samples and study samples were analysed in duplicate. All of the samples were tested in the same assay. Statistical analysis Full 168-h AUC values were calculated using the linear trapezoidal rule. Median AUC values, standard deviation values and coefficient of variation percentages were calculated for each treatment group. Correlation analysis for both drugs was performed by linear regression analysis (NCSS Software; NCSS Statistical Software, Kaysville, UT, USA). 202 Results Baseline patient characteristics are summarized in Table 1. A total of 22 adult patients participated in the study. In the peginterferon alpha-2a group (n=10), the mean age was 47 ±8 years and body weight ranged from 55–88 kg. Among the 12 patients receiving peginterferon alpha-2b, the mean age was 40 ±10 years and body weight ranged from 48–91 kg. Area-under-the-curve measurements are shown in Table 2 and are graphically depicted in Figures 1 and 2. Table 1. Baseline characteristics Characteristic Gender, % male Mean age, years Race, Caucasian, % Mean HCV RNA, log10 IU/ml HCV genotype 1, % Mean ALT, IU/l Cirrhosis/transition to cirrhosis, % Mean body weight, kg (range) Mean body mass index, kg/m2 (range) Peginterferon alpha-2a (n=10) Peginterferon alpha-2b (n=12) 70 47 ±8 90 5.7518 ±0.3777 70 106 ±65 20 75 40.4 ±10 100 5.6474 ±0.5039 50 102 ±43 16 73.9 (55–88) 72.8 (48–91) 26.1 (23–37) 24.1 (19–28) Table 2. AUC by body weight for patients receiving a single dose of peginterferon alpha-2a (flat-dosed) or peginterferon alpha-2b (body-weight dosed) Peginterferon alpha-2a (40 kD) Peginterferon alpha-2b (12 kD) Patient body weight, kg AUC, µg·h·ml–1 Patient body weight, kg AUC, µg·h·ml–1 55 62 72 73 73 74 75 83 84 88 1505.8 732.92 1399.19 1659.55 1582.39 1028.13 1124.42 694.65 1306.57 381.77 48 55 65 66 70 73 75 79 80 82 90 91 Median 1141.54 427.66 37.46 90.15 116.5 47.23 45.47 70.02 36.8 105.48 64.67 71.42 115.59 53.34 93.54 75.87 27.91 36.79 SD CV, % AUC, area-under-the-curve; CV, coefficient of variation; SD, standard deviation. © 2005 International Medical Press Body weight and AUC for peginterferon alpha Figure 1. Peginterferon alpha-2a: relationship between body weight and AUC 1800 AUC 1400 1000 600 200 55.0 63.8 72.5 81.3 Body weight, kg 90.0 AUC, area-under-the-curve. Figure 2. Peginterferon alpha-2b: relationship between body weight and AUC 120 AUC 95 70 45 20 40.0 55.0 70.0 85.0 Body weight, kg 100.0 AUC, area-under-the-curve. For peginterferon alpha-2a, there was no correlation between body weight and AUC (P=0.2127, R2=0.1865) (Figure 1). However, considerable interpatient variability in the AUC was observed for peginterferon alpha-2a [coefficient of variation (CV): 37.5%]. Similarly, for peginterferon alpha-2b, there was no correlation between body weight and AUC (P=0.7710, R2=0.0089) (Figure 2). Despite dosing by body weight, marked interpatient variability in the AUC was observed for peginterferon alpha-2b (CV: 38.7%). Antiviral Therapy 10:2 Discussion In this study, the AUC for 0–168 h after single-dose administration of both peginterferon alpha-2a and peginterferon alpha-2b in patients with chronic hepatitis C did not correlate with body weight. Furthermore, considerable interpatient variability in AUC measurements was observed for both compounds, presumably related to factors other than body weight [1]. For peginterferon alpha-2b, interpatient variability in AUC was equal to that for peginterferon alpha-2a, despite dosing of peginterferon alpha-2b by body weight. The results observed for peginterferon alpha-2b are similar to those previously reported [10,11]. A population-based pharmacokinetic analysis for peginterferon alpha-2b revealed between-subject variability of greater than 40% for several pharmacokinetic parameters [10]. Although body weight had a statistically significant effect on apparent clearance, the effect was small and of questionable clinical relevance. Such findings have led some investigators to question whether peginterferon alpha-2b really needs to be dosed by body weight at all, particularly if the aim of bodyweight dosing is to reduce interpatient variability in the clinical response to the drug [1]. Our results suggest that dosing peginterferon alpha-2b based on body weight does not achieve more consistent drug exposure. Studies of flat-dosing peginterferon alpha-2b, that is, uniform dosing regardless of body weight, thus appear to be warranted. The results observed for peginterferon alpha-2a are compatible with those from previous observations. In a population-based pharmacokinetic study of patients with chronic hepatitis C, body weight accounted for only approximately 1% of the observed betweensubject variability for volume of distribution and apparent drug clearance ([1]; data on file, HoffmannLaRoche). Although the interpatient variability in these pharmacokinetic parameters was considerable – approximating 50–80% [1] – the lack of a significant relationship to the subject’s body weight was compatible with our results. Furthermore, the volume of distribution for peginterferon alpha-2a is approximately 6–14 l [1], in contrast to 0.99 l/kg for peginterferon alpha-2b [11]. Given that peginterferon alpha-2a is probably cleared primarily by the hepatic route [12], its volume of distribution would presumably not vary with body weight to such an extent that body weight could explain any observed interpatient variabilities in its pharmacokinetics. Body weight appears to be an important factor predictive of a sustained virological response (SVR) to both standard interferon and pegylated interferon plus ribavirin therapy in patients with chronic hepatitis C [3,4]. Nonetheless, some controversy prevails over 203 R Bruno et al. whether body weight is truly an independent factor within the context of age and gender [13]. It may be advantageous to take body weight into consideration when determining peginterferon dosing in the obese patient. Data from clinical trials have demonstrated a lower rate of SVR to peginterferon alpha-2a among patients with higher body weight (>85 kg) than among those with lower body weight (<85 kg) [3,5,14]. Response rates among patients receiving fixed-dosed peginterferon alpha-2a were 49% for patients weighing >85 kg and 60% for those weighing <85 kg [14]. However, body-weight dosing of peginterferon alpha2b produced an SVR in 48% of patients weighing >85 kg, versus 58% of patients weighing <85 kg [15]. Thus, dosing by body weight did not alter the effect of body weight on sustained virological response. These data are compatible with our AUC results. Overall, these observations suggest that the effect of body weight will not be overcome simply by employing a dosing regimen based on body weight for either peginterferon alpha-2a or peginterferon alpha-2b. Patients with higher body weights may possibly require higher levels of drug exposure to overcome the resistance to pegylated interferon and ribavirin therapy associated with increased body weight, perhaps resulting from associated hepatic steatosis [16]. Increasing the drug dosage would increase the drug exposure for both drugs. Our data suggest that a bodyweight dosing regimen would not offer any advantage in this setting. As we previously reported [7], it is the pharmacokinetic and resultant viral kinetic profile of the peginterferon therapy, rather than whether the agent is dosed according to body weight, which may influence response to therapy. Among the 10 patients in our pilot study who received peginterferon alpha-2a, serum concentrations of the drug increased continuously over time, reaching maximal serum levels from 48–168 h, and the drug was detectable in all 10 patients at 168 h. In contrast, of the 12 patients who received peginterferon alpha-2b, the drug was undetectable in seven (58%) patients at 120 h and in 11 (92%) patients at 168 h. Although mean HCV-RNA levels at weeks 1 and 4 were not significantly different between the groups, at week 12, the mean HCV-RNA value was significantly lower in the peginterferon alpha-2a group than in the peginterferon alpha-2b group (2.8126 vs 3.8726; P<0.01). We concluded that once-weekly administration of peginterferon alpha-2b may be insufficient for continuous interferon exposure, and we proposed that twice-weekly administration might help avoid increases in viral replication as interferon levels decline [7]. A large, randomized multicentre study is currently underway in the USA, comparing the pharmacokinetic 204 and viral kinetic properties of peginterferon alpha-2a plus ribavirin with peginterferon alpha-2b plus ribavirin in patients with difficult-to-treat chronic hepatitis C genotype 1 infection and high baseline HCV-RNA levels. Interim results (planned study duration, 12 weeks) in 44 patients [17] showed that trough serum levels of drug were above the limit of quantification (250 pg/ml) for all patients receiving peginterferon alpha-2a at weeks 3 and 4, but they were below the limit of quantification (148 pg/ml) in some of the patients receiving peginterferon alpha-2b. After 8 weeks of treatment, reductions in mean serum HCV-RNA level were greater for patients treated with peginterferon alpha-2a than for those receiving peginterferon alpha-2b. In conclusion, our study has demonstrated that AUC measurements after a single initial injection for both peginterferon alpha-2a and peginterferon alpha2b do not vary with body weight. The results confirm the hypothesis, based on other pharmacokinetic data and the properties of peginterferon alpha-2a, that there is no rationale for considering a dosing regimen for peginterferon alpha-2a based on body weight. In patients receiving peginterferon alpha-2b, dosing by body weight did not achieve more consistent AUC measurements and, hence, drug exposure. Dosing by body weight to reduce interpatient variability in clinical response or to overcome the adverse effects of increased body weight on sustained virological response is not effective for peginterferon alpha-2b and is not supported by the observed results for peginterferon alpha-2a. Acknowledgements The authors are indebted to Dr Antonello Rigamonti and Prof Martino Recchia for their invaluable help. Industry support Peginterferon alpha-2a study drug was provided by Hoffman-LaRoche. References 1. Lamb MW & Martin NE. Weight-based versus fixed dosing of peginterferon (40kDa) alfa-2a. Annals of Pharmacotherapy 2002; 36:933–935. 2. Wurtz R, Itokazu G & Rodvold K. Antimicrobial dosing in obese patients. Clinical Infectious Diseases 1997; 25:112–118. 3. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J & Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New England Journal of Medicine 2002; 347:975–982. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M & Albrecht JK. Peginterferon alfa-2b plus ribavirin 4. © 2005 International Medical Press Body weight and AUC for peginterferon alpha compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358:958–965. 5. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H Jr, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A & Ackrill AM; PEGASYS International Study Group. Peginterferonalpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Annals of Internal Medicine 2004; 140:346–355. 6. DiBisceglie AM & Hoofnagle JH. Optimal therapy of hepatitis C. Hepatology 2002; 36(Suppl 1):121–127. 7. Bruno R, Sacchi P, Ciappina V, Zochetti C, Patruno S, Maiocchi L & Filice G. Viral dynamics and pharmacokinetics of peginterferon alpha-2a and peginterferon alpha-2b in naive patients with chronic hepatitis C: a randomized, controlled study. Antiviral Therapy 2004; 9:491–497. 8. PEGASYS® (Peginterferon alfa-2a). Prescribing Information. Roche Laboratories Inc, Nutley, NJ, USA. 9. PegIntron® (Peginterferon alfa-2b). Prescribing Information. Schering-Plough Corporation, Kenilworth, NJ, USA. 10. Jen JF, Glue P, Ezzet F, Chung C, Gupta SK, Jacobs S & Hajian G. Population pharmacokinetic analysis of pegylated interferon alfa-2b and interferon alfa-2b in patients with chronic hepatitis C. Clinical Pharmacology & Therapeutics 2001; 69:407–421. 11. Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Salfi M & Jacobs S. Pegylated interferon alpha2b: pharmacokinetics, pharmacodynamics, safety, and 12. 13. 14. 15. 16. 17. preliminary efficacy data. Clinical Pharmacology & Therapeutics 2000; 68:556–567. Modi MW, Fulton JS, Buckmann DK, Wright TL & Moore DJ. Clearance of pegylated (40 kDa) interferon alfa-2a is primarily hepatic. Hepatology 2000; 32(Suppl):371A. Poynard T, McHutchison J, Goodman Z, Ling MH & Albrecht JK. Is an ‘a la carte’ combination interferon alfa2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group. Hepatology 2000; 31:211–218. US Food and Drug Administration. Center for Drug Evaluation and Research. Peginterferon alfa-2b. Proceedings from the Antiviral Drugs Advisory Committee. 12 December 2001. http://www.fda.gov/ohrms/dockets/ac/ cder01.htm#Anti-Viral. Last accessed 16 September 2004. US Food and Drug Administration. Center for Drug Evaluation and Research. Peginterferon alfa-2b. Proceedings from the Antiviral Drugs Advisory Committee. 14 November 2002. http://www.fda.gov/ohrms/dockets/ac/ cder02.htm#AntiViralDrugs. Last accessed 16 September 2004. Hickman IJ, Powell EE, Prins JB, Clouston AD, Ash S, Purdie DM & Jonsson JR. In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy. Journal of Hepatology 2003; 39:1042–1048. DiBisceglie AM, Rustgi VK, Thuluvath P, Mitchell D, Reem G, Lyons MF, Ondovik MS, Lopez-Talavera JC & Hamzeh F. Pharmacokinetics and pharmacodynamics of pegylated interferon alfa-2a or alfa-2b with ribavirin in treatment naive patients with genotype 1 chronic hepatitis C. Hepatology 2004; 40(Suppl 1):Abstract LB18. Received 17 December 2004, accepted 18 February 2005 Antiviral Therapy 10:2 205