ClIn. Ph, rmarok' ncl. 19(S): )9(1..399.

1990
031 2-5%)/90/00 Io.o)90/S0S.00JO
CI Adls Interna uonal umlled
AU n lhlS rncrved.
CI"M(l(XI "2

Clinical Pharmacokinetics of Interferons

Robert J. Wills
Department of Drug Metaboli sm, R,W, Johnson Pharmace Ul ical Resea rch InsllilIle.
Rari lan, Ne w Jersey. USA

Contents Sum mary ............. .................................... 390

I. Protem SU'UCII,I!'e .....••.. ••...••...••...••....••....••...••••..••••..
, ,,_ .....•....................•............. 39 1
1.1 Interferons-<> ........ ,............................... 391
1.2 In terferon., ............................................ _ ...... ....... __ ____ ___ ___ __
I,) In terferon •.., ..................................................................... ................................. 391'"
2. AUIYS in B,0I01.1I;31 ManlC'e$ .............................................. ........................................ 391
2.1 Bloassays .................... ........................................................ _ ........................................ 391
2.2 Im munolosical Assays .............................................. .................. ...392
3. Funda me ntal PharmarokinetiC$ ................ .. ............ 392
3.1 Absorpti on ................. .............................................. .. ............. 392
3. 2 Distribution ..... .......................................................... .. .............. 393
3.3 Calobolism/ Eliminalion .................................... ... _......................................... 394
4. Relal ionship to Ad verse Events .......................................... .. ..................................... 394
5. Relal ionship to Bioloeical Response ..................................... .. ....................... 395
6. Dru, lntel1lelions . .................................. .. ..................... 397
7. Anl ibocilCS ............................................................ _................. ........................ 397

Interferons a re a famil y o f pro te ins s hown t o be effecti ve in the treatm ent of vi ral
(co nd ylomata. llCum inata) and neoplastic (ha iry cell leukaemia and AIDS-related
Kaposi' s sa rco ma ) di seases. To date, th e cli nical ulilit y of the interferons has been ham·
pered by a n inco mplete understanding o f their mechanism of action. However, Ihere is
supportin. evidence that th e route of adm ini stration. i.e. the pharmaookinetic beha vio ur,
is an im portant treatment variable.
The pharmacokinetics of interferon s ha ve been fairl y well descri bed. The decline in
serum concentratio ns of interferon is rapid afier intra veno us admin isuation. The vo lume
of d istri bu tion approlt imates 20 to ~ of bod yweigtll. Wock in a nimals sugests that
the catabolism of nterferons
i falls within the natural handl in, of proteins. Oeara nce val·
ues vary (4.8 to 48lIh) across the fam ily o f interferons and probabl y reflect the natu ral
internal diJCStio n and turnover of these proteins. Terminal elimination half·li ves ra nge
fro m 4 t o 16 hors.u I to 2 ho urs and 2S to 35minutes for a. {J and l. res pecti vely.
Intramusc ular and subcutaneous admin istrat io n of in terkro ns cr and {J results in
pro tracted but fairl y good abso'llti o n: >SOCIiI fo r interferon ... and 30 10 70% for inter·
fero n"'l.
Interferon therapy is associated with ad verse evenls wh k h are usuall y m ild and reo
versible. Temporal relati o nships exist between the dqree and duratio n of ad\'erse effects
Pharmacoklnel!cs of Interferons 391

and the route of administration. Attempts to relate inducible biochemical markers. such
as 2'.5'-oligoadenylate synthetase activlIy. to dose or concentration have met with some
success although alterations in these markers have nOt betn shown to relate to clinical
responsc. Interferons can reduce hepatic drug metabolism but further work is needed
before a true asscssmenl of clinical relevance can be made. Finally. antibodies 10 the
interferons have been detected but the clinical relevance is still unknown.

I. Protein Structure L2 Interferon·1t

Human interferon·1t is a s ngle

Interferons are classified into 3 major groups
which reflect antigen ic and structural differentia·
tion. Interferon·a (leucocyte interferons) is pro-
duced by B lymphocytes. null lymphocytes a nd
macrophages which can be induced by foreign. vi·
rus· infected. tumour or bacterial cells. Interferon·
fJ (fibroblasl interferon) is produced by fibroblasts.
epithelial cells and macrophages which can be in·
duced by viral and other foreign nucleic acids. In-
terferon.')' (i mm une interferon) is produced by ac-
tivated T lymphocytes which are induced by foreign
antigens. Readers are referred to the review by
Rashidbaigi and Pestka (1 988) for indepth detail
and references on interferon protein structure.
1.1 Interfcrons-a
Human interferon-a is a family of more than 15
subtypes. with molecular size ranging from 17.5 to
23kD and containing 165 or 166 amino acid resi·
dues with about 80% sequence homology. The sec·
ondary structure of human interferons-a shows 55
to 70% a·helix content and less than 16% ,B·sheet
content. These interferons. except fo r subtypes B
and D. have 4 cysteine residues at positions 1,29,
99 and 139 which arc i nvolved in disul phide bonds
(I to 99 and 29 to 139). Subtype B has a cysteine
residue at position 98 instead of 99. and subtype
D has an additional cysteine residue at position 86.
In general. human interferons-a do not contain N·
linked glycosylation sites. Subtype H is an excep-
tion. with 2 poten tial N·linked g1ycosylation sites
at positions 2 and 78. These interferons lend to be
acid ic, with isoeltX:tric points of 5.7 to 7.0.
i species. T he mo-
lecular size of the natural glycoprotein is 23kD and
it cOrilains 166 am ino acid residues. 21 of which
are removed during secretion from cells. Inter·
feron -It has 29% structural homology to interferon·
a. The secondary struclUre shows 36% a·helix con·
tent and 33% ,B·sheet content. with cysteine resi·
dues at poSitions 17, 31 and 141. A potential N·
linked glycosylation site exists at position 80. The
isoelectric point falls between 6.8 and 7.8.
1.3 Interferon.),
Human interferon-')' is heterogeneous, the mo-
lecular size depend ing on glycosylation and pos-
sibly oligomerisation. The 20kD protein is N·linked
g1ycosylated at posi tion 28. while the 25kD protein
is g1ycosytated at posi tions 28 and 100. Higher mo-
lecular weights of 50 to 70kD have been reponed,
suggesting oligomerisation. Interferon.,), is com·
posed of 143 am ino acids; it has no statistically
significant sequence homology to interferon-a and
.fj. Cysteine residues exist at positions I and 3. It
is acid labile and high ly basic, with an iso-
electric point of 8.6 to 8.7.
2. Assays in Biological Matrices
2.1 Bioassays
T he bioassay is t he most commonly used tech·
nique fo r determining concentrations of interfer·
ons in biological fluids. Most of the interferon
bioassays rely on the same biological end·point:
q uantification of a viral cytopath ic effect of host
cells (Rubinstein et at. 1981). Host cells and the
virus selected may differ depending on the inter·
392
fercn of interest. In general, biological fluid con-
taining interferon is added 10 plates seeded with
monolayers of host cells and incubated; the me-
dium from each well is aspirated, followed by a
washing of the cells. The cells are thcn challenged
with a cytopathic virus. The interferon titre is rcad
as the reciprocal of the dilution in which 50% of
the cell monolayer is protected, determined by vis-
ual inspeelion (Hawkins et at 1985; Rubinstein et
a!. 1981) or spectrophotometric detection (Arm-
stro ng 1981; McManus 1976). Sensitivity of the as-
says in sera 3rc on thc order of 5000 U/ L.
2.2 Imm unological Assays
The other types of assay used for interferon de-
termination in biological fluids ha ve an immuno-
logical basis and 3rc more amenable to pharmaco-
kinetic use. In general , biological fluid containing
interferon is incubated with an anti-interferon anti-
body bound to a solid phase such as a polystyrene
bead. A second antibody, either radiolabelled
(Protzman et al. 1985; Secher 1981 ; Walker et al.
1982) or coupled with horseradish peroxidase (Gal-
lati 1982) and specific for a second epitope of in-
terferon, is added and incubated to effect binding
or 'sandwiching' of the interferon. Following wash-
ing, beads containing the radiolabelled antibody are
subjected to scintillation counting or, in the second
case, the horseradish peroxidase is enzymatically
removed and quantified spectrophotometrically.
The sensitivity of the assays in sera is similar to
that ofthe bioassays; but the advantage of this type
of assay is increased reproducibility and precision.
3, Fundamental Pharmacokinetics
Interferon doses and concentrations are defincd
in units of biological activity whose magnitude is
derived fro m the established activity ofa reference
standard. Since these standards can (and often do)
differ, it makes littlc sense to compare or discuss
dose and serum concentrations, quantitatively, for
a given family of interferons, when the values are
derived from different sources. Thi s constraint is
elm. PharmaCQkmel. 19 (5) 1990
respected in the pharmacokinetic review which fol-
lows.
3.1 Absorption
Absorption in the classical sense refers to oral
absorption. Oral absorption of intact proteins, such
as the interferons, is unlikely because of the natural
proteolytic digestive capabilities of the gastrointes-
tinaltract. Although research is still ongoing in the
area of oral delivery of peptides and proteins, suc-
cess is notanticipated in the near future in the case
of large proteins such as interferons.
Alternative sites for absorption have been ex-
plored with the interferons. The system ic absorp-
tion of these substances from sites other than the
gastrointestinal tract has been remarkably good,
considering the size of these molecules. Intramus-
cularly and subcutaneously administered inter-
feron-a (Borncmann et al. 1985; Budd et al. 1984;
Hawkins et al. 1984; Gutterman et al. 1982; Ornata
et al. 1985; Quesada et al. 1983; Radwanski et al.
1987; Shah et at. 1984: Sherwin et al. 1982; Wells
et at. 1988; Wills et al. 1984) and nonglycosylated
interferon..,. (Kunrock et at. 1985; Thompson et
al. 1987) are well absorbed: >80% for interferon-a
and 30 to 70% for interferon-"Y. These routes ex-
hibit protracted absorption, which results in max-
imum serum or plasma concentrations occurring
after 1 to 8 hours, followed by measurable concen-
trations for 4 to 24 hours after injection for both
interfcron-a and -"Y (fig. I). Maximum serum con-
centrations following these routes of administra-
tion are at least an order of magnitude less than
the highest concentration after an equal dose given
intravenously. The absorption of interferon-,B from
muscle or skin has not been suffieient to produce
serum concentrations much above the limits of as-
say detection (Billiau et al. 1979; Hawkins et al.
1985; Quesada et aJ. 1982).
Other routes of administration (inhalation
(Kin nula et al. 1989), intralesional (Green et al.
1984). intranasal (Davies et al. 1983; Phillpolls et
at. 1984; Sarno et al. 1984), intraperitoneal (D'AC-
quislo et al. 1988), intrathecal (Sm ith el al. 1982),
in traventricular (Jaeobs et al. 1986; Smith et al.
Pharmacolunt'lI('S of Intrrfnons
'00000
~ "000
g several orders of magnitude over the measurable
I
'000
'00
I 10 35 minutes for Inlerferon-,,(. Serum concentra-
"
.,
,.
o
Tome (hi " " 20
Fig. I. M~an !.erum Inlcrft'ron",,-2a oonrcnlr.ilIiOnS aller a
smglt' 36 x IO"U dosr admmlslered as a 4O-mlnule mlra-
>("nous infusion (0 ). an InlramuS('ular m,ecllon (_ ) and a
subcutanrous mJCCllon (. ) 10 health) subjects (from Wills rl
1982) and ocular (Turner et al. 1989)J ha"e been
evaluated In clinical slUdies. For the most pan.
these alternatIve rOUles were attempts to Improve
the deliver) of Interferon to Sites not eastly acces-
sible f rom systemic admimstration. These dosing
strategies have provided adequate concentrations
of interferon In CSF. lymph. nasal mucosa and
peritoneal flUid but have not led to clinical success.
undoubtedl) reflecting the lack o f understanding of
the Inherent mechanism of interferon aC1\on.
3.2 Dlstnbutlon
Interferons have been eval uated WIth a variety
of dosage regimen frequencies ranging from inter-
mittent to continuous adminIstration. Although
defim live pharmacokinetics have not been re-
poned In all cases. enough information IS a,'allable
to define then baSIC dlspoSlllon . Serum Inlerferon
concentrations following inlravenous admimstra-
tion decline rapldl) in a biexponenlial manner for
Inlerferon--o (Bornemann et al. 1985; Rad .... anski et
al. 1987; Shah et al. 1984: Smtih et al. 1985: Wells
et al. 1988: Wills & Spiegel 1985: Wills et al. 1984)
and Interferon-Ii (Grunberg et al. 1987; Hawkins et
al. 1985: Liberati el al. 1989: McPherson & Tan
393
1980; Sarna et al. 1986). or monoexponenlially i n
the case of interferon-..,. (Gunerma n 1.'1 al. 1984;
Kunrock et al. 1985. 1986: Vadhan-Raj et al. 1986).
Ini lial in terferon concentrations arc known t o fall
serum concentralLon-time course (fig. I). Terminal
elimination half-lives ra nge from 4 to 16 hours for
inlerferon--o. I 10 2 hours for interferon-Ii and 25
tions are generally measurable for between 8 a nd
24 hours after injection of interferon--a and u p to
4 hours after injection for interferon-Ii and -'Y. re-
spective-ly.
The volu me of dist ribution is sim ilar for bot h
-0 and -..,.. ranging from 12 to 40L (Bornemann e t
al. 1985; Gullerman et al. 1984; Kurzrock et al.
1985; Shah et al. 1984: Wills et al. 1984). Although
this "olume is not physiological. it approximates
to 20 to 60% of body weight. Information regarding
in terferon~ has not been reponed.
There has not been a great deal of research in-
vestigating the tissue d si tribution of interferons i n
humans. most of this work being restricted to ani-
mals. One area that has been studied in huma ns is
that of penetration across the b lood-brain barrier.
Panially purified (Smi th et al. 1982). natural (Pri-
estman et al. 1982) or recombinant (Jablecki et al.
1983; ManlnO & Singhakowi nla 1984; Smith et al.
1985) Interferons do not readily cross the blood-
brain bamer Intact after in travenous. inlramus-
cular or subcutaneous administration. These data
must ultimately be reconciled with the occurrence
of neurotox ici ty. a common side effect of inter-
feron therapy.
Many studies have focused on the presence of
nalural interferon in a variety of diseases, Unfor-
IUnalely. there is no one review which collates this
informal1on. The pomtlO be made is thai the pres-
ence of endogenous Interferon has been detected in
tissue and flUids of a wide variety of seemingly un-
related dlscases. By way of example. interferon has
been found 10 the bram (Salonen 1983) a nd CS F
(Dcgre et al. 1976) of patients with multiple scle-
rOSIS. in the lesions of patients with recurrent herpes
labialis (Overall et al. 1981) and psoriasis (Bjerke
et al. 1983). and in the synovial fl uid of patients
394
with rheumatoid arthritis (Oegre et at 1983). The
clinical relevance of these findings has yet to be
determined, although recent papers by Heremans
and Billiau (1989) (discussing the potential role of
interferons in inflammatory disease) and Khan et
al. (1989) shed some light on this issue.
3.3 Catabolism/Elimination
There have been no definitive studies of Ihe ca·
tabolism of the interferons in humans, although a
number have been performed in animals. As ex-
pected, the catabolism of Ihe 3 types of interferon,
whether native or cloned, falls within the natural
handling of proteins, a process which is similar
across most species. Therefore, it is reasonable to
discuss the catabolism orlhc interferons in animals
with Ihe assumption that it is applicable to hu-
mans.
The catabolism of interferon-a, including sub-
types, has been the most extensively studied of the
3 types. In general, a-interferons are filtered through
the glomeruli of the kidney via luminal endocy-
tosis followed by proximal tubular reabsorption
(Bino et al. 1982a,b; Bocci et al. 1981a,b, I982b).
During reabsorption, the a -interferons undergo
proteolytic degradation by lysosomal enzymes (Bino
el aJ. 1982a,b; Bocci et al. 1984; Rosenberg et al.
1985), so that negligible amounts are excreted in-
tact in the urine. Several studies have assessed the
effect of nephrectomy on the pharmacokinetics of
interferon-a: as expected, the clearance was sig-
nificantly decreased in nephrectomised rabbits
(Bocci et al. 1981a) and rats (Tokazewski-Chen et
al. 1983). Consistent with the above findings is the
fact that the liver has been shown to playa small
role in the catabolism of a-interferons (Bocci et al.
1982a, 1983b).
Both interferon-,6 and interferon....,. undergo renal
catabolism, but to a much smaller extent than the
a·interferons. The work performed thus far sug·
gests that liver catabolism is the predominant
pathway of el imination for interferon-,6 and -"'}'
(Bocci et al. 1982a, 1983a, 1985b). Natural inter-
feron-tJ and interferon....,. contain sialic acid groups,
classifying them as g1ycosylated proteins, whose
C/U!. Pharmucoklnf'l. 19 (5) /990
liver catabolism is supponed by the literature
(Ashwell & Morell 1974). In I study (Tokazewski-
Chen et al. 1983) the clearance ofinterferon-tJ, both
natural (glycosylated) and cloned, was unaltered in
nephrectomised rats; this finding suppons the hy-
pothesis of a nonrena1 pathway for catabolism.
Other organs, such as lung and muscle, have been
suggested as potential catabolic sites for interfer-
ons. A more detailed review of interferon cata-
bolism is provided by Bocci (1985a).
Whatever the true mechanism, negligible
amounts of intact interferon or even polypeptide
degradation products are excreted in urine or bite,
which is consistent with the natural conservation
of amino acids inherent to the catabol ism of pro-
teins (Bocci \985a). Therefore, the clearance of in-
terferons reflects the natural internal digestion and
turnover of these proteins. The clearance of leu-
cocyte interferons has been reponed to range from
4.86 to 21 L/h (Bornemann et aJ. 1985; Shah et al.
1984; Smith et al. 1985; Wills et aJ. 1984) or 24 LI
h/ m 2 (Radwanski et al. 1987). For fibroblast in-
terferon the clearance is much higher, 19.38 to 31.5
L/ h/ m 2 (Sarna et al. 1986), wh ile that of immune
interferon falls between the two at 12.66 to 32.4 LI
h (Gutterman et aJ. 1984; Kurzrock et al. 1985).
4. Relationship t oAd~e'se Events
Treatment with any of the interferons is asso-
ciated with adverse events which are usually mild
and reversible (Gutterman et at 1984; Hawkins et
al. 1985; Jones & Itri 1986; Kurzrock et al. 1985;
McPherson & Tan 1980; Quesada et at. 1982; Spie-
gel 1985; Van Der Burg et al. 1985). The adverse
effects can be classified as either acute or of later
onset, and are qualitatively similar across the in-
terferon families. Adverse events of later onset in-
clude fatigue, anorexia and weight loss, and are
often dose-limiting. The acute events, which in-
clude influenza-like symptoms of fever. chills,
myalgias, headache, arthralgia and diaphoresis,
usually occur within a few hours of drug admin-
istration and can often be ameliorated by pretreat-
ment with paracetamol (acetaminophen). The se-
verity of these events tends to increase with the
PharmacokmCl1cs of Interferons
administered dose and is dependent on the route
of administration. In panicular, more prolonged
and continuous exposure to interferon, such as that
occurring with intramuscular and subcutaneous in-
jections compared with intravenous bolus admin-
istration, will result in an increased severity and
duration of adverse events (Borden et al. 1988:
Hawkins et al. 1985: Kurzrock et al. 1986; Thomp-
son et al. 1987: Wills et al. 1984). Tolerance to these
acute events usually develops within the first few
weeks of treatment, independently of dose or
schedule, so they are rarely of concern in long term
therapy (Borden et al. 1988: Jones & Itri 1986;
Thompson et al. 1987).
Fever is the most prevalent of the acute adverse
reactions. It is postulated that leucocyte and fibro-
blast interferons induce fever through the stimu·
lation of the hypothalamus to release prostaglandin
E2 (Oinarello et al. 1984). Immune interferon ap-
pears to elicit fever through the induction of in·
terleukin-l (Vi1cek el al. 1985). Although the re·
lationship belween dose (concentration) and
toxicity docs nOI appear to be direct. it has been
suggested Ihat the severity of fever induced by leu·
cocyte interferon depends on exceeding and main-
taining serum concentrations above an undefined
threshold level (fig. 2) [Wills et al. 1984]. Similarly,
a saturable induction mechanism has been postu-
lated for immune. interferon (Brown et al. 1987).
The threshold concept. along with the develop-
ment of tachyphylaxis, provided the rationale for
subsequent dosage regimens. Low doses were ad-
ministered inilially with the hope of reducing the
frequency and severity of the acute adverse effecls
while inducing tolerance: doses were increased to
achieve the larget dosage o nce tachyphylaxis had
occurred.
5. Relationship to Biological Response
Interferons display a broad spectrum ofaclivity
comprising antiviral, antiproliferative and immu·
noregulatory propenies. The biological response to
these substances is complex and incompletely char·
acterised: ahhough it is known that most of Ihe
biological effects of interferons stem from induel-
'95
~fo-rrrTT,,-rrrTT,,-r"
o 4 8 12 16 ro N U ~ ~
Tme since Irsl observation (h)
FIg. 2. Mean change in body temperatu re after a single 36)(
I()6U dose of interfcron ....·2a given as II 4O-minutc intravcn-
ous Infusion (0). an intramuscular injection (_ ) and a sub-
cutancous injection (e ) to hcalthy subjects. Changes in body
tcmp('raturc were more severe lind of longer duration aftcr
in tra muscular and subcutaneous injection than aftcr intra·
,'cnous inJection. evcn though serum concentrations were
conSiderably highcr after thc latter (rrom Wills ct al. 1984,
with p('rmission).
ble actions. Interferons induce 2',5'-oligoadenylate
synthetase activity, activated natural killer (NK)
cells. 1f2-microgiobulin, other cell surface proteins
and Olher enzymes (Borden el al. 1988; Goldstein
et al. 1989; Grunberg et al. 1987: Gutterman et al.
1984; Kurzrock et al. 1986; Lotzova et al. 1983;
Merritt el al. 1986; Sarna el al. 1986; Thompson
el al. 1987; Vadhan-Raj el al. 1986; Witter et al.
1987).
These inducible biochemical markers have been
determined in many clinicallrials investigating the
clinical utility of the interferons using a wide range
of doses, routes of administration and regimens.
Nevertheless, attempts to define a dose-response
relationshi p have been less than successful. For ex-
ample, investigators reponed a positive dose re-
sponse between elevated 1f2-microglobuli n and
doses of interferon"'1" administered as 6-hour in-
fusions (Vadhan-Raj et al. 1986), while other in-
vestigators using the same interferon"'1" preparation
at the same dosage found no such relationship
(Kurzrock et al. 1986). Olher investigators em-
ploying bolus doses, I-hour infusions, or intra-
muscular administration reponed no clear-dose re-
sponse relationships using interferons-a, -If or "'1",
3% C/in. Pharmacokwe1. /9 (5) /990

although some trends have been observed (Gold-
stein et at 1989; Grunberg et al. 1987; Gutterman
et al. 1984; Kurzrock et al. 1986; Lotzova et 31.
1983; Thompson et al. 1987),
More rigorous attempts to define a dose-
response relationship involved interferon-<r and the
induction of 2',5'-oligoadenylatc synthetase activ-
ity. Merritt and colleagues (1986) determined 2',5'-
oligoadenyJale synthetase activity as a function of
single and multiple doses of human Iymphoblast-
o id interfero n-a given intramuscularly. A 2 - to 6-
fo ld increase in 2',5'- activity was reported over a
300-fold dose range given intramuscularly (fig. J).
Witter el31. (1987) conducted a similar study using
a reco mbinant inlerferon-a and reported a dose re-
sponse over a 6O-fold d ose range after intramus-
cular administration. The same investigators
measured the resistance to vesicular stomatitis vi-
rus in vitro after collecting peripheral blood mono-
nuclear cells from the study subjects, and observed
a dose response here also. Both Merritt et al. ( 1986)
and Witter et al. (1987) reported that the pro-
longed, continuous exposure to interferon follow-
ing intramuscular administration was associated
with a longer duration of 2',5'- activity relative to
the same dose given intravenously, suggesting a de-
pendence on ro ute of administration. Another not-
able observation reponed by Witter et al. ( 1987)
was the induction of an antiviral state in the a~
sence of adverse events, which challenges the
speculation that the constitutional symptoms as-
sociated with a viral in fection are pan of the host
antiviral response and are necessary for antiviral
activity.

"
"
" ,,.
30 5 x loS

25 2 x loS

,,,. ~
~
20

'!, 5 x 10"' ~
2
" !
t
~
.~

V
x
i "
2 10"'
E
~
0
> ,<>,
"
•<
" 5
<4 x 103

0 ,, r r I I r ,
0 loS 3 x loS 10' 3 x 10' 107 3 x 107
Interferon dose (U)
Fig. 3. Mean (:t SEM) values of peak serum interferon (e ) and pea k post-tll'atment 2'.S'-oligoadenylate (2-SA) $ynthe!ase
activity in peripheral mononuclear cells c-> in 6 patients aft er intramUSoCular injection s with 6 doses of interferon .... (from
Merrill et al. 1986. wit h permission).
Pharmacokmeucs of Inlerferons
Another consideration is the relationship of bio-
logIcal response to serum concentrations. Seru m
concentrations of interferons following a si ngle dose
are generally nondetectable aHer 24 hours. The in-
duced 2'.5'- activity, and other actions indUCIble by
interferon, last several days. In the case of in ter-
feron-~. biological response was elicited in the tOial
absence of measurable serum concentrations aHer
either in tramuscular or subcutaneous injecl10n
(Goldstein et a1. 1989: Quesada et a1. 1982). Thus,
serum concentrations arc not likely to be useful in
gauging an optimal biological response.
Even though select dose-response relationships
have been established, none of the biological re-
sponses induced by interferon have been shown to
relate to clinical response, so that assigning clinical
meaning to these relationships becomes extremely
difficult. This lack of understanding undoubtedly
contributes to the limited clinical utility of the in-
terferons.
6, Drug Interactions
Precedence for drug metabolism interactions
between interferons and other therapeutic agents
has been established in animal models. Work con-
ducted in mice has shown that interferon-a (Par-
kinson et at. 1982; Secor & Schen ker 1984: Taylor
et al. 1985) and interferon-,), (Sonnenfeld et al. 198 1)
ca n reduce hepatic drug metabolism through a re-
duction in the level of microsomal cytochrome
P450. Clinically. Williams and Farrell (1986) re-
ported a 16% decrease in the clearance of phena-
zone (antipyrine) after a isngle therapeutic intra-
muscular dose of interferoo-a to 9 patients being
treated for chronic active hepatitis B, suggcstinglhat
interferon may reduce hepatic metabolism in hu-
mans. These same investigators assessed the inter-
action between a single therapeutic intramuscular
dose of interferon-a and a single 5 mg/kg in tra-
venous dose of aminophylline in 5 patien ts with
chronic hepatitis B and in 4 healthy subjects (Wil-
liams el a!. 1987). The effect of interferon-a on
theophylline metabolism was highly variable and
showed a 50% reduction in median clearance from
0.042 (0.0 16 to 0.464) to 0.022 (0.011 to 0.086) If
397
h/ kg and a 40% prolongation of median half-life
from 6.3 (0.85 to 13. 1) to 10.7 (4.8 to 27.4) hours.
In another study. where a 4mg/kg intravenous dose
of aminophylline was given to 12 healthy subjects
after a 3-day course of interferon-a administered
dail y by Intramuscular injection . a 51% reduction
in theophylline clearance and prolongation in half-
life was observed (Jonkman et al. 1989). Further
studies arc needed bcfore a true assessment of the
climcal relevance of this interaction can be made.
7, Antibodies
The issue surroundi ng antibody formation and
the clinical significance was addressed at a work-
shop and publ ished recently (Von Wussow & Bor-
den 1989). It was not possible to achieve definitive
statements regarding antibody incidence, relative
product antigenicity or the clinical significance of
human interferon antibodies. Carefully designed
prospective st udies. which would control for vari-
ables such as dosage regimens. roule of adminis-
tration. cu mulati ve dose, length of treatment, and
sampling time and frequency. and standardised
antibody detection methodology. need 10 be de-
veloped or implemented to satisfactorily ans .....er the
question of the clinical relevance of human inter-
feron antibodies.
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CO~SpOndcn~ and n:pnnlil: Dr Ro#xrl J Wills. R.W. Johnson
Pha rmaceu u o:al Rrstlrch InS"lu,c. P.O. Bo~ 300. Route 202.
Rln ... n. NJ 08869. USA