DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1612 Absorption, Distribution, and Elimination. Oral administration
does not result in detectable IFN levels in serum or increases in
2-5(A) synthetase activity in peripheral blood mononuclear cells (used
as a marker of IFN’s biologic activity). After intramuscular or subcutaneous
injection of IFN-α, absorption exceeds 80%. Plasma levels
are dose related, peaking at 4-8 hours and returning to baseline by
18-36 hours. Levels of 2-5(A) synthetase in peripheral blood
mononuclear cells show increases beginning at 6 hours and lasting
through 4 days after a single injection. An antiviral state in peripheral
blood mononuclear cells peaks at 24 hours and decreases slowly
to baseline by 6 days after injection. Intramuscular or subcutaneous
injections of IFN-β result in negligible plasma levels, although
increases in 2-5(A) synthetase levels may occur. After systemic
administration, low levels of IFN are detected in respiratory secretions,
CSF, eye, and brain.
Because IFNs induce long-lasting cellular effects, their activities
are not easily predictable from usual pharmacokinetic measures.
After intravenous dosing, clearance of IFN from plasma occurs
in a complex manner (Bocci, 1992). With subcutaneous or intramuscular
dosing, the plasma t 1/2
of IFN-α ranges is variable, 3-8 hours.
Elimination from the blood relates to distribution to the tissues, cellular
uptake, and catabolism primarily in the kidney and liver.
Negligible amounts are excreted in the urine. Clearance of IFN-α2B
is reduced by ~80% in hemodialysis patients (Uchiharaa et al., 1998).
Attachment of IFN proteins to large inert polyethylene glycol
(PEG) molecules (pegylation) slows absorption, decreases clearance,
and provides higher and more prolonged serum concentrations that
enable once-weekly dosing (Bruno et al., 2004). Two pegylated IFNs
are available commercially: peginterferon alfa-2a (PEGASYS) and
peginterferon alfa-2B (PEGINTRON). PegIFN alfa-2B has a straightchain
12,000-Da type of PEG that increases the plasma t 1/2
from
~2-3 hours to ~30-54 hours (Glue et al., 2000). PegIFN alfa-2a consists
of an ester derivative of a branched-chain 40,000-Da PEG bonded to
IFN-α2A and has a plasma t 1/2
averaging ~80-90 hours. PegIFN alfa-
2A is more stable and dispensed in solution, whereas pegIFN alfa-2B
requires reconstitution prior to use. For pegIFN alfa-2A, peak serum
concentrations occur up to 120 hours after dosing and remain
detectable throughout the weekly dosing interval (Bruno et al., 2004);
steady-state levels occur 5-8 weeks after initiation of weekly dosing
(Keating and Curran, 2003). For pegIFN alfa-2A, dose-related maximum
plasma concentrations occur at 15-44 hours after dosing and
decline by 96-168 hours. These differences in pharmacokinetics may
be associated with differences in antiviral effects (Bruno et al., 2004).
Increasing PEG size is associated with longer t 1/2
and less renal clearance.
About 30% of pegIFN alfa-2B is cleared by the kidneys;
pegIFN alfa-2A also is cleared primarily by the liver. Dose reductions
in both pegylated IFNs are indicated in end-stage renal disease.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Untoward Effects. Injection of recombinant IFN doses of ≥1 to
2 million units (MU) usually is associated with an acute influenzalike
syndrome beginning several hours after injection. Symptoms
include fever, chills, headache, myalgia, arthralgia, nausea, vomiting,
and diarrhea. Fever usually resolves within 12 hours. Tolerance
develops gradually in most patients. Febrile responses can be moderated
by pretreatment with antipyretics. Up to one-half of patients
receiving intralesional therapy for genital warts experience the
influenzal illness initially, as well as discomfort at the injection site,
and leukopenia.
The principal dose-limiting toxicities of systemic IFN are
depression, myelosuppression with granulocytopenia and thrombocytopenia;
neurotoxicity manifested by somnolence, confusion,
behavioral disturbance, and rarely, seizures; debilitating neurasthenia
and depression; autoimmune disorders including thyroiditis and
hypothroidism; and uncommonly, cardiovascular effects with
hypotension and tachycardia. The risk of depression appears to be
higher in chronically infected HCV than in HBV patients (Marcellin
et al., 2004). Elevations in hepatic enzymes and triglycerides, alopecia,
proteinuria and azotemia, interstitial nephritis, autoantibody formation,
pneumonia, and hepatotoxicity may occur. Alopecia and
personality change are common in IFN-treated children (Sokal et
al., 1998). The development of serum neutralizing antibodies to
exogenous IFNs may be associated infrequently with loss of clinical
responsiveness. IFN may impair fertility, and safety during pregnancy
is not established. IFNs can increase the hematological toxicity
of drugs such as zidovudine and ribavirin and may increase the
neurotoxicity and cardiotoxic effects of other drugs. Thyroid function
and hepatic enzymes should be monitored during IFN therapy.
Pegylated IFNs are generally better tolerated than standard
IFNs, with discontinuation rates ranging from 2-11%, although the
frequencies of fever, nausea, injection-site inflammation, and neutropenia
may be somewhat higher. Laboratory abnormalities, including
severe neutropenia and the need for dose modifications, are
higher in HIV-co-infected persons.
Therapeutic Uses. Recombinant, natural, and pegylated IFNs currently
are approved in the U.S., depending on the specific IFN type,
for treatment of condyloma acuminatum, chronic HCV infection,
chronic HBV infection, Kaposi’s sarcoma in HIV-infected patients,
other malignancies, and multiple sclerosis. In addition, interferons
have been granted orphan drug status for a variety of rare disease
states including idiopathic pulmonary fibrosis, laryngeal papillomatosis,
juvenile rheumatoid arthritis, and infections associated with
chronic granulomatous disease.
Hepatitis B Virus. In patients with chronic HBV infection, parenteral
administration of various IFNs is associated with loss of HBV DNA,
loss of HBeAg and development of anti-HBe antibody, and biochemical
and histological improvement in ~25-50% of the patients.
Lasting responses require moderately high IFN doses and
prolonged administration (typically 5 MU/day or 10 MU in adults
and 6 MU/m 2 in children three times per week of IFNα-2B for 4
to 6 weeks) (Sokal et al., 1998). Plasma HBV DNA and polymerase
activity decline promptly in most patients, but complete
disappearance is sustained in only about one-third of patients or
less. Low pretherapy serum HBV DNA levels and high aminotransferase
levels are predictors of response. Sustained responses are
infrequent in those with vertically acquired infection, anti-HBe
positivity, or concurrent immunosuppression owing to HIV.
PegIFN alfa-2A appears superior to conventional IFN alfa-2A in
HbeAg-positive patients (Cooksley et al., 2003), and treatment
(180 μg once weekly for 24-48 weeks) is associated with normalization
of aminotransferases in ~60% and sustained viral suppression
in ~20% of HBeAg-negative patients (Marcellin et al.,
2004). Responses with seroconversion to anti-HBe usually are
associated with aminotransferase elevations and often a hepatitislike
illness during the second or third month of therapy, likely
related to immune clearance of infected hepatocytes. High-dose