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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
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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).
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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
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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.
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Antiviral Therapy 10:2
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