A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Infergen Pharmacology, Pharmacokinetics, Studies, Metabolism - Interferon alfacon-1
Infergen Pharmacology, Pharmacokinetics, Studies, Metabolism - Interferon alfacon-1
CLINICAL PHARMACOLOGY
General
Interferons are a family
of naturally occurring small protein
molecules with molecular weights of 15,000 to 21,000 daltons that
are produced and secreted by cells in response
to viral infections or
to various synthetic and biological
inducers. Two major classes of interferons have been identified
(ie type-I and type-II). Type-I interferons include a family
of more than 25 interferon
alphas as well as interferon
beta and interferon
omega. While all alpha
interferons have similar biological
effects, not all the activities are shared by each alpha
interferon and
in many cases, the extent of activity varies substantially for each
interferon subtype.
All type-I interferons share common biological
activities generated by binding of interferon
to the cell-surface receptor,
leading to the production of several interferon-stimulated gene
products. Type-I interferons induce pleiotropic biologic
responses which include antiviral,
antiproliferative and immunomodulatory effects, regulation
of cell surface
major histocompatibility antigen (HLA class
I and class II) expression
and regulation of
cytokine expression. Examples of interferon-stimulated gene
products include 2'5' oligoadenylate synthetase
(2'5' O.S. and ß-2
microglobulin.
The antiviral, antiproliferative,
NK cell activation, and
gene-induction activities of Infergen have been compared with other
recombinant alfa
interferons in in vitro assays and have demonstrated similar
ranges of activity. Infergen exhibited at least five times higher
specific activity
in vitro than Interferon alfa-2a and Interferon alfa-2b.2
Comparison of Infergen with a WHO
international potency
standard for recombinant
interferon alfa (83/514) revealed that the specific
activity of Infergen
in both an in vitro antiviral
cytopathic effect
assay and an antiproliferative
assay was 1 x 109 units/mg. However, correlation
between in vitro activity
and clinical activity
of any interferon
is unknown.
Pharmacokinetics and Pharmacodynamics
The pharmacokinetic properties of Infergen have not been evaluated
in patients with chronic
hepatitis C. Pharmacokinetic
profiles were evaluated in normal,
healthy volunteer subjects
after SC injection
of 1, 3, or 9 mcg Interferon alfacon-1. Plasma levels of Infergen
after SC administration of any dose
were too low to be detected by either ELISA
or by inhibition of viral
cytopathic effect.
However, analysis of
Infergen-induced cellular products (induction of 2'5' OAS and ß-2
microglobulin) after treatment in these subjects revealed a statistically
significant, dose-related increase in the area
under the curve (AUC)
for the levels of 2'5' OAS or ß-2 microglobulin induced
over time (p < 0.001
for all comparisons). Concentrations of 2'5' OAS were maximal at
24 hours after dosing, while serum
levels of ß-2 microglobulin appeared to reach a maximum
24 to 36 hours after dosing. The dose-response relationships observed
for 2'5' OAS and ß-2 microglobulin were indicative of biological
activity after SC administration
of 1 to 9 mcg Infergen.
Preclinical Experience
All interferons have been shown to be highly species
specific. Antiviral activity of Infergen was observed in the rhesus
monkey LLC cell line
and golden Syrian hamster
BHK cell line. Antiviral
activity of Infergen
in the golden Syrian hamster
was confirmed further in vivo.3 Pharmacokinetic
studies of Infergen in golden Syrian hamsters and rhesus monkeys
demonstrated rapid absorption
following SC injection. Peak serum concentrations of Infergen were
observed at 1 hour and 4 hours in golden Syrian hamsters and in
rhesus monkeys, respectively. Subcutaneous bioavailability was high
in both species, averaging
99% in golden Syrian hamsters and 83% to 104% in rhesus monkeys.
Clearance of Infergen averaging 1.99 mL/minute/kg in golden Syrian
hamsters and 0.71 to 0.92 mL/minute/kg in rhesus monkeys, was due
predominantly to catabolism
and excretion by the
kidneys. The terminal half-life of Infergen following SC dosing
was 1.3 hours in golden Syrian hamsters and 3.4 hours in rhesus
monkeys. Upon 7-day multiple
SC dosing, no accumulation of serum
levels was observed in golden Syrian hamsters.
In preclinical
toxicology studies
in golden Syrian hamsters and rhesus monkeys, administration
of Infergen at doses of up to 100 mcg/kg/day was associated with
decreased body weight,
decreased food consumption,
and bone marrow suppression.
High-dose chronic exposure
at doses of 10 to 100 mcg/kg/day (50- to 500-fold higher than the
maximum clinical
dose given daily) in rhesus
monkeys was not tolerated for greater than 1 month, due to the development
of vascular leak syndrome.
Reproductive toxicity
studies in pregnant
rhesus monkeys and golden Syrian hamsters demonstrated an increase
in fetal loss
in hamsters treated with Infergen at doses of greater than 150 mcg/kg/day,
and in rhesus monkeys at doses of 3 and 10 mcg/kg/day. The Infergen
toxicity profile
described is consistent with the known toxicity
profile of other alfa
interferons.4
CLINICAL EXPERIENCE: RESPONSE TO
INFERGEN
Infergen was studied in an open-label dose
escalation study using 3, 6, 9, 12, or 15 mcg
administered three times per
week (TIW) to patients with compensated liver
disease secondary
to chronic hepatitis
C virus (HCV) infection.
The 15 mcg dose
was the maximal tolerated dose. All doses demonstrated an acceptable
safety profile and preliminary
evidence of efficacy.
The efficacy of 3
and 9 mcg doses of Infergen
in the treatment of
chronic HCV infection
was examined in a randomized, double-blind clinical
trial involving 704 patients previously untreated with alfa interferon.
Patients were 18 years or older, had compensated liver
disease, tested positive
for HCV RNA, and had elevated
serum alanine
aminotransferase (ALT) concentrations averaging > 1.5 times the
upper limit of normal.
Staging of chronic liver disease
was confirmed by a liver
biopsy taken within 1
year prior to enrollment. Other causes of chronic
liver disease
were ruled out prior to randomization. Notable exclusion
criteria were decompensated liver
disease, thyroid abnormality, or history
of depression.
Efficacy of Infergen therapy
was assessed on an intent
to treat basis and was determined by measurement of serum
ALT concentrations at the
end of therapy (24 weeks)
and following 24 weeks of observation after the end of treatment.
Serum HCV RNA
was also assessed using a quantitative
reverse transcriptase polymerase
chain reaction
(RT-PCR) assay with a
lower limit of sensitivity
of 100 copies/mL. Liver histology
was assessed by comparing the histology
activity index
(HAI) score5 of a pretreatment biopsy specimen
with the HAI score from
a specimen obtained
24 weeks after cessation of interferon
therapy.
Patients enrolled in the study were randomized to one of three
treatment groups: Infergen at a dose
of 3 mcg (n = 232), Infergen
at a dose of 9 mcg (n =
232), or Interferon alfa-2b recombinant
[IFN alfa-2b, Intron® A (Intron® is a registered trademark
of the Schering Corporation)] at a dose
of 3 million international units (IU) (approximately 15 mcg) (n
= 240). All patients were scheduled to receive their respective
interferons SC TIW for 24 weeks (end of treatment). Following treatment,
patients were observed for an additional 24 weeks to assess durability
of ALT normalization (end
of post-treatment observation). In
all patients, a complete response was defined as a decrease in serum
ALT concentration
to at or below the upper limit
of normal (48 U/L) at
the end of the post-treatment
observation period, even if ALT
normalization
had not been observed at the end
of treatment. Complete response
was dependent on two consecutive normal
serum ALT
values determined 4 weeks apart. Reduction of HCV
RNA to < 100 copies/mL
was measured as a secondary
efficacy endpoint
(two consecutive measurements).
Sustained response
rates by ALT normalization
and HCV RNA
reductions to below detectable limits are included in Table 1. Among
the Infergen treatment groups in this study, the 9 mcg
dosage arm
demonstrated a similar efficacy profile
when compared to the IFN alfa-2b dosage
arm. The 3 mcg Infergen dosage
arm had lesser efficacy;
3% of patients receiving 3 mcg Infergen had sustained reductions
in their ALT concentrations
to within the normal
range and 3% had sustained
reductions in HCV RNA
to below detectable limits.
|
Table 1. Rates (95% CIa) of ALT
Normalization
and HCV RNA
Reductions to Below Detectable Limits
|
| |
End of 24-week Treatment
|
End of Observation
(Sustained Response Rate)
|
| |
Infergen 9 mcg
|
IFN alfa-2b
3 Million IUb
|
Infergen 9 mcg
|
IFN alfa-2b
3 Million IUb
|
| Normalized ALT |
39% (33%, 46%)
|
35% (29%, 41%)
|
17% (12%, 22%)
|
17% (13%, 22%)
|
| HCV RNA
Negative |
33% (27%, 39%)
|
25% (19%, 31%)
|
9% (6%, 14%)
|
8% (5%, 13%)
|
- a CI = Confidence Interval.
- b 3 million IU IFN alfa-2b is equivalent
to approximately 15 mcg
IFN alfa-2b.
|
In this study, liver
biopsies were taken at baseline
and at the end of post-treatment observation. Similar improvement
in liver histology, assessed
by HAI score,5 was observed in the 9 mcg
Infergen (68%), 3 mcg Infergen
(63%), and IFN alfa-2b (65%) dosage
arms.
Subsequent treatment
with 15 mcg of Infergen
was evaluated in an open-label clinical trial in 107 patients who
had failed initial therapy
with either 9 mcg Infergen
or 3 million IU (approximately 15 mcg) IFN alfa-2b. Of these patients,
74/107 had failed to normalize ALT
concentrations during either the initial
treatment period
or the post-treatment observation period, while 33/107 achieved
a normal ALT
concentration
during initial treatment,
but experienced relapse
(return of abnormal
ALT concentration) during
post-treatment observation. Patients were assessed for normalization
of ALT (ALT response rate)
and HCV RNA
reduction to <
100 copies/mL (HCV response
rate) at the end of 24 weeks
of observation. Response rates (expressed as fraction of patients,
percentage of patients, and 95% confidence interval
of percentage) are presented for all patients and two subsets of
patients: patients who had relapsed following initial
therapy and patients
who had never normalized following initial
therapy.
Overall 16/107 [15% (9-23% CI)] patients had a sustained ALT
response. Of patients who had relapsed following initial
therapy 10/33 [30% (16-49%
CI)] had a sustained ALT
response and 6/74 [8%
(3-17% CI)] who never normalized their ALT
concentration
had a sustained ALT response.
Overall 10/107 [9% (5-17% CI)] patients had a sustained HCV
response (< 100
copies/mL). Of patients who had relapsed following initial
therapy 8/32 [25% (11-43%
CI)] had a sustained HCV
response and 2/75 [3%
(0-9% CI)] who never had a reduction
in HCV RNA
to < 100 copies/mL, had a sustained HCV
response.
Serum antibody levels
were measured in all patients using both an Infergen-binding radioimmunoassay
and an IFN alfa-2b-binding ELISA. A patient
was considered to have developed binding antibodies if, using serum
samples from two consecutive time points, a positive
response was detected
in either assay. The number of patients developing positive
binding antibody responses
in either assay was similar in the 9 mcg
Infergen (11%) and 3 million IU IFN alfa-2b groups (15%). The titer
of neutralizing antibodies to interferon
was not measured. Sustained ALT
response rates in patients
treated with Infergen who developed binding antibodies (4/25) were
similar to sustained ALT
response rates in patients
who did not develop detectable antibody
titers (40/195). The most frequently observed time
to first antibody response
was week 16 of interferon treatment. Following cessation of interferon
therapy, the number
of patients with a positive
antibody response
declined during post-treatment observation.
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