| |
Differences between
Pegasys and Peg Intron
The Two Pegylated Versions of Interferon alfa Are Not Identical
by Harvey S. Bartnof, MD
FDA approval for two pegylated versions of interferon alfa * are expected
this year. Pegasys (peginterferon alfa-2a) from Hoffman-La Roche and Peg
Intron (peginterferon alfa-2b) from Schering are the two formulations that
are under FDA review.
Widespread availability of these newer formulations will have a great impact
upon the treatment of chronic hepatitis C. The differences and similarities
of the two formulations were discussed during a satellite meeting at
Digestive Disease Week 2000. The title was "Assessment of Novel Hepatitis C
Therapies: Pegylated Interferons and Beyond." It was sponsored by
Professional Postgraduate Services and supported by an unrestricted
educational grant from Hoffman-La Roche.
Teresa L. Wright, MD, from the Veterans Administration Medical Center at the
University of California at San Francisco reviewed the "pharmacology" (study
of drugs) and "pharmacokinetics" (movement and distribution of drugs) of
pegylated interferon alfa.
Variable anti-HCV effects Dr. Wright first addressed why pegylated
interferon
alfa would be expected to have better anti-HCV (hepatitis C virus) effects
than the non-pegylated versions. When non-pegylated interferon alfa (NPIA)
is
injected at the standard dose of 3 million international units (MIU) 3-times
weekly, the "trough" levels in-between doses are quite low. During the last
12 hours of the 2-day dosing interval, there is no detectable drug. This is
due to the short "half-life" (amount of time until half of an original
amount
is remaining) of NPIA (3-5 hours) that leads to inadequate antiviral
activity
in-between dosing, with HCV rebound that is observed with monotherapy.
These factors likely contribute to the "disappointing sustained response
rate" of NPIA monotherapy. It is also possible that those fluctuations could
contribute to certain of the drug's side effects. Dr. Wright showed a graph
depicting HCV viral load decreases during a 2-week period using different
"therapeutic" doses or regimens. When the standard FDA dose of 3 MIU 3-times
weekly of NPIA is given for two weeks, the HCV RNA initial decreases by
approximately 1.5 log (31-fold) during the first couple days and then
returns
towards normal. Then there is a slow gradual decline to slightly less than 1
log (10-fold) viral reduction from baseline after two weeks. The second
example was daily NPIA or standard dose NPIA plus ribavirin. Each of those
options leads to an HCV viral load reduction of approximately 3 log
(1,000-fold) reduction by two weeks. The third example was pegylated
interferon once weekly: this led to a viral load reduction of approximately
3.5 log (3,100-fold) after two weeks.
Principles of "Pegylation"
Then Dr. Wright discussed the principals of "pegylation." Polyethylene
glycol
(PEG) is a "non-toxic polymer" (a substance with a high "molecular weight")
that is easily excreted in the urine, due to its being soluble in water. The
size of the pegylated polymer depends upon the number of repeating units of
carbon atoms attached to hydrogen and oxygen. "PEG" also can be linear or
branched. It can be attached to the "base" substance (interferon alfa, in
this example) by different types of protein linkages.
These links or bonds may alter the stability of the PEG-protein and may also
affect its activity. The larger or branched PEGs lead to a longer, sustained
absorption period. They also have a "reduced clearance" by the kidney.
(Clearance is measured as liters or volume per hour per kilogram of body
weight.) These larger/branched PEGs are removed from the underlying
interferon in the liver. Whereas, smaller and linear PEGs will have a less
sustained and shorter absorption period.
They have a "greater clearance" by the kidney and are removed from the
underlying interferon in the kidney, not the liver. Dr. Wright said that
there is a "trade off between increased PEG size and reduced specific
activity." The point of significance will only be determined by clinical
studies of the two types. Overall, PEG attachment to interferon alfa leads
to
a longer half-life of the interferon. This occurs due to decreased
"clearance" by the kidney and reduced "proteolysis" (slower breakdown of
protein). In addition, PEG attachment to interferon leads to lowered
"antigenicity" of interferon. This means less probability that the immune
system would make antibodies against interferon that can occur among those
who use NPIA. PEG attachment also leads to increased chemical and thermal
(heat) stability of the "base" substance interferon.
Differences between Pegasys and Peg Intron
Dr. Wright then reviewed some differences between Pegasys and Peg Intron.
Pegasys uses a larger 40 "kilodalton" PEG that is attached to interferon in
a
branched fashion. Whereas, Peg Intron uses a smaller 12 "kilodalton" PEG
that
is attached to interferon in a linear fashion. Each formulation has a PEG to
interferon ratio of one to one. Distribution of the two formulations is
somewhat different. Like NPIA, Peg Intron is distributed widely throughout
the body. Whereas, Pegasys is distributed to the blood and organs, including
the liver.
This means that there may be some compartments within the body that Pegasys
does not penetrate. Other differences include the half-lives. Due to it's
longer and branched-chain PEG, Pegasys has a half-life ("terminal
elimination") of 50-80 hours. Whereas, due to it's shorter and linear-chain
PEG, Peg Intron has a half-life of 30-50 hours. (Note that NPIA or
non-pegylated interferon alfa has a half-life of only 3-5 hours.)
Later, Dr. Wright characterized the half-lives of Pegasys and Peg Intron as
"similar." The "clearance" of the formulations from the body is decreased
when compared to NPIA. Peg Intron has a 10-fold decreased clearance, while
Pegasys has a 100-fold decreased clearance. Each formulation will have
increased blood levels with multiple dosing. When using the dose of 1
microgram per kilogram, Peg Intron had a maximal blood serum (no cells)
concentration approximately 24 hours after a dose.
With multiple weekly doses, the peak level of Peg Intron was approximately
0.8 nanograms per milliliter, with a gradual taper towards zero after the
sixth day.
Whereas, Pegasys achieves maximal concentration 80 hours after a dose, using
its standard dose of 180 micrograms once weekly. With multiple weekly doses,
the peak level was approximately 25 nanograms per milliliter, which
decreases
to approximately 20 nanograms per milliliter at the end of the seventh day
(the end of the dosing interval). Dr. Wright said that Pegasys definitely
has
some "protection from degradation" and Peg Intron "likely" has the same.
Doses used for these calculations for Pegasys was 180 micrograms once
weekly,
while that for Peg Intron ranged between 0.035 to 2 micrograms per kilogram
once weekly. Molecular differences were also addressed by Dr. Wright. The
amino acids involved in PEG attachment to interferon in Peg Intron were
lysine and histidine. Whereas, the attachment in Pegasys is predominantly
lysine. The clinical relevance of that difference was not discussed. A
subtle
difference in the attachment to interferon of the linear versus branched PEG
forms also was discussed.
Even though each form attaches in a "one to one ratio" with interferon, more
than one linear PEG theoretically could attach to each interferon in Peg
Intron.
"This "could in theory lead to aggregation or blockage of the active site"
[of interferon]. Whereas, the single branched PEG in Pegasys "binds at a
specific site, [while the] active site likely remains unhindered." It should
be emphasized that these differences are theoretical."
Summing up the differences between Pegasys and Peg Intron, Dr. Wright
numerated the following factors.
"Clearance" of Pegasys is less than that of Peg Intron.
Pegasys "is metabolized by the liver;" Peg Intron "is metabolized by the
kidney."
The "area-under-the-curve" (total) concentration of Pegasys is "more
consistent" than Peg Intron.
Dr. Wright said that the "increase in levels [of drug] with time may result
in"……"either, both or neither" of the following: increased efficacy or side
effects of [Pegasys] over [Peg Intron].
Similarities between Pegasys and Peg Intron
The similarities of Pegasys and Peg Intron are as follows. Both can be
administered once weekly subcutaneously (under the skin). The half-life of
each is significantly longer than NPIA (non-pegylated interferon alfa). Dr.
Wright described the half-lives of each as being "similar" to one another.
Both have a favorable "pharmacokinetic" or "PK" profile that "supports
improved efficacy over standard interferons." In addition, multiple dosing
of
each leads to increased blood serum levels.
Final Thoughts Dr. Wright ended her talk by reviewing that changing the
"pharmacokinetics" of interferon alfa with pegylation has resulted in once
weekly dosing and much reduced differences between peak and trough (lowest)
levels of active drug. The optimal dose of either formulation will depend
upon the results of clinical trials.
Reviewing the differences of Pegasys and Peg Intron, Dr. Wright said that
the
significance of the various differences between the two formulations would
only be determined by clinical studies.
Studies to date clearly show that pegylated interferon alfa monotherapy
leads
to greater levels of sustained HCV virologic responses. The sustained
virologic response rates will likely be even greater when combined with
ribavirin and/or other anti-HCV agents.
· Note that all four generic versions use the spelling 'alfa' and not
'alpha' interferon.
· 6/2/00 Reference: Wright TL. Pegylated interferons: pharmacology and
pharmacokinetics. Assessment of Novel Hepatitis C Therapies: Pegylated
Interferons and Beyond, satellite symposium at Digestive Disease Week 2000;
May 21-24, 2000; San Diego, California.
|
Overview of Pharmacokinetic Properties of Pegasys
|
|
|
|
|
This article reviews Pegasys
and its distribution in the body, metabolism, elimination,
in the elderly/cirrhotics/renal impairment. In the end what
matters most is the clinical effect of a drug. In other
words, in this case, does it reduce your viral load to
undetectable and sustain it, and well does the drug do this
in large numbers of patients; and is it safe. The FDA (Food
and Drug Adminstration) is reviewing the application for
approval for this drug now. The effectiveness and safety of
Pegasys has been reported in a number of studies presented
at conferences. The public reporting of this data by the FDA
should take place at the end of its review simultaneous to
approval. Data so far presented at conferences can be read
on the NATAP website.
Excerpted from full report from Adis Intl., written by
Caroline Perry and Blair Javis;
www.adis.com; report supported by grant from Roche,
manufacturer of Pegasys.
Peginterferon-a -2a (40kD) (Pegasys) is well absorbed after
single subcutaneous doses in healthy volunteers or multiple
subcutaneous doses in patients with chronic hep-atitis C.
Three to 8 hours after a single 180 ug dose of the drug,
'substantial' concentrations (values not reported) of
peginterferon-a -2a (40kD) were detected in the serum of 10
healthy volunteers. Peginterferon-a -2a (40kD) was delivered
to the systemic circulation at a sustained rate; the mean
maximum serum concentration (Cmax) of peginterferon-a -2a
(40kD) was 14.2 µg/L and was reached in mean time (tmax) of
78 hours. After single 180 ug doses of peginterferonao -2a
(40kD), serum peginterferon-a -2a (40kD) concentrations were
sustained for longer than concentrations of interferon-a -2a
in healthy volunteers. In 16 patients with chronic hepatitis
C who received multiple doses of peginterferon-a -2a (40kD)
180 µg/week, the peginterferon-a -2a Cmax was 25.6 µg/L and
the tmax was 45 hours. After single 180ug doses (n = 14),
Cmax and tmax values were 15.4 µg/L and 80 hours,
respectively; steady-state concentrations of the drug were
attained 5 to 8 weeks after initiation of the once-weekly
regimen in these patients.
Peginterferon-a -2a (40kD) is cleared by both the liver and
kidney and the liver plays an important role in the
metabolism of the drug. Because of its large size and
branched nature, peginterferon-a -2a (40kD) undergoes
reduced renal clearance compared with that of standard
interferon-a , thus prolonging hepatic exposure to the
pegylated interferon. Pegylation resulted in a >100-fold
reduction in the renal clearance of interferon-a -2a in 10
volunteers who received a single 180 ug dose of
peginterferon-a -2a (40kD). Metabolic products of
peginterferon-a-2a (40kD) are eliminated via the kidneys.
However, clearance via the kidneys does not appear to be
extensive as the pharmacokinetics of the drug in patients
with chronic renal impairment (creatinine clearance values
>20 ml/min; >1.2 L/h) are not appreciably different from
those in patients with normal renal function.
In patients with chronic hepatitis C and cirrhosis, the
terminal half-life of peginterferon-a -2a (40kD) was 70 to
90 hours. Peginterferon-a -2a (40kD) showed no significant
effects on drug metabolism mediated by CYP2C9, 2C19, 2D6 and
3A4 isoenzymes in healthy nonsmoking male volunteers.
However, as documented with interferon-a, the clearance of
theophylline (metabolised by CYP1A2) was significantly
reduced (compared with baseline) in volunteers receiving
multiple doses of peginterferon-a -2a (40kD).
Editorial note: in patients with HIV who take HIV
antiretrovirals, there is some potential for interaction of
ribavirin with NRTI medications. Ribavirin is an NRTI
without HIV or HCV antiviral effect. In vitro studies show
interaction between ribavirin and 3TC, AZT, d4T, and ddI.
Ribivarin reduced exposure to all of these but increased ddI
exposure. In human clinical studies there has not been
evidence that these potential interactions are of clinical
significance, but studies are ongoing. HIV viral load does
not appear to increase when IFN/RBV is administered along
with an HIV regimen. Its been suggested this could be due to
the effect of interferon in reducing HIV viral load, or
perhaps there is no clinical effect.
Elderly Volunteers
The absorption of peginterferon-a -2a (40kD) after a single
180 ug dose is slower in healthy elderly men aged >60 years
(n = 12; tmax 116 hours) than in healthy young men aged 18
to 25 years (n = 12; tmax 81 hours). [25] Peginterferon-a
-2a (40kD) Cmax values were similar in elderly and young men
(9.1 and 10.3 µg/L), but the elderly group had greater
systemic exposure to the drug (area under the serum
concentration-time curve values were 1663 and 1295 µg h/L,
respectively) suggesting that the drug should be used with
caution in elderly patients with chronic hepatitis C.
However, this was not considered by the investigators to
result in an increase in the biological activity of the
drug.
Distribution
Peginterferon-a -2a (40kD) displays restricted
biodistribution in patients with chronic hepatitis C [31]
and in animals, [29] with highest concentrations occurring
in the liver where the drug can be most effective. [29] The
drug was recovered from injection site tissue, blood, liver,
kidneys and spleen in rats after a single intravenous or
subcutaneous dose of radiolabelled peginterferon-a -2a
(40kD). Amounts of radioactive peginterferon-a -2a (40kD)
were highest in the liver and kidney (6.9 and 1.4%,
respectively) 14 days after the single intravenous dose;
similar results were obtained after a single subcutaneous
dose of the drug. [29] Con centrations of peginterferon-a
-2a (40kD) were <1% in all other organs examined.
Metabolism and Elimination
Peginterferon-a -2a (40kD) is cleared by both the liver and
the kidney and the liver plays an important role in the
metabolism of the drug. [29] Because of its large size and
branched nature, peginterferon-a -2a (40kD) undergoes
reduced renal clearance compared with that of standard
interferon-a , thus prolonging hepatic exposure to the
pegylated interferon. Pegylation resulted in a >100-fold
reduction in the renal clearance of interferon-a -2ain 10
vol-unteers who received a single 180 ug dose of
peginterferon-a -2a (40kD); clearance values for
peginterferon-a -2a (40kD) and standard interferon-a were
0.08 and 11.8 L/h (data from previous investigations),
respectively. [30] Peginterferon-a -2a (40kD) had a mean
clearance of 0.060 L/h in 16 patients with chronic hepatitis
C who received peginterferon-a -2a (40kD) 180 µg/week for 48
weeks. [31]
Peginterferon-a -2a (40kD) was shown to be cleared mainly by
hepatic metabolism in rats [after an initial period of >24
hours when 14 C-labelled peginterferon-a -2a (40kD) remained
unmetabolised in the liver]. [29] The liver : blood ratio of
radio-labelled peginterferon-a -2a (4kD) concentrations was
greater than that of interferon-a , suggesting that
peginterferon-a -2a (40kD) provides the liver with greater
exposure to interferon-a than standard interferon-a. [30]
Metabolic products of peginterferon-a -2a (40kD) are
eliminated via the kidneys. However, clearance via the
kidneys does not appear to be extensive as the
pharmacokinetics of the drug in patients with varying
degrees of chronic renal impairment (CLCR values >20 ml/min;
>1.2 L/h) are not appreciably different from those in
patients with normal renal function. [32] Elimination
occurred at a consistent rate during the 14-day period after
administration of a single intravenous or subcutaneous dose
in rats. [29] During this time, proportions of the total
radioactive dose eliminated in the urine and faeces were 51
and 9.6%, respectively. In patients with chronic hepatitis C
and cirrhosis, the terminal half-life (t 1 Ú2 ) of
peginterferon-a -2a (40kD) [70 to 90 hours] was similar to
that in healthy volunteers (77 hours). [34] The t 1 Ú2 of
peginterferon-a -2a (40kD) was longer in elderly than in
young men (110 vs 61 hours). [25]
|
|
|