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

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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 ............. I.

Protem SU'UCII,I!'e

.................................... 390 .....••.. ••...••...••...••....••....••...••••..••••.. , ,,_ .....•....................•............. 39 1

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

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3.

4. 5. 6. 7.

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

391

Pharmacoklnel!cs of Interferons

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 Interferons are classified into 3 major groups which reflect antigen ic and structural differentia· tion. Interferon·a (leucocyte interferons) is produced 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. Interferon.')' (i mm une interferon) is produced by activated 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 exception. 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.

L2 Interferon·1t Human interferon·1t is a s ngle i species. T he molecular 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 molecular size depend ing on glycosylation and possibly 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 molecular 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 isoelectric 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·

elm. PharmaCQkmel. 19 (5) 1990

392

fercn of interest. In general, biological fluid containing interferon is added 10 plates seeded with monolayers of host cells and incubated; the medium 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 visual inspeelion (Hawkins et at 1985; Rubinstein et a!. 1981) or spectrophotometric detection (Armstro 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 determination in biological fluids ha ve an immuno-

logical basis and 3rc more amenable to pharmacokinetic use. In general , biological fluid containing interferon is incubated with an anti-interferon antibody 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 (Gallati 1982) and specific for a second epitope of interferon, is added and incubated to effect binding or 'sandwiching' of the interferon. Following washing, 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

respected in the pharmacokinetic review which follows.

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 gastrointestinaltract. Although research is still ongoing in the area of oral delivery of peptides and proteins, success is notanticipated in the near future in the case of large proteins such as interferons. Alternative sites for absorption have been explored with the interferons. The system ic absorption of these substances from sites other than the gastrointestinal tract has been remarkably good, considering the size of these molecules. Intramuscularly and subcutaneously administered interferon-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 exhibit protracted absorption, which results in maximum serum or plasma concentrations occurring after 1 to 8 hours, followed by measurable concentrations for 4 to 24 hours after injection for both interfcron-a and -"Y (fig. I). Maximum serum concentrations following these routes of administration 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 assay 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'ACquislo et al. 1988), intrathecal (Sm ith el al. 1982), in traventricular (Jaeobs et al. 1986; Smith et al.

Pharmacolunt'lI('S of Intrrfnons

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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 accessible 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 intermittent to continuous adminIstration. Although defim live pharmacokinetics have not been reponed In all cases. enough information IS a,'allable to define then baSIC dlspoSlllon . Serum Inlerferon concentrations following inlravenous admimstration 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

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 several orders of magnitude over the measurable 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 10 35 minutes for Inlerferon-,,(. Serum concentrations 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. respective-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 investigating the tissue d si tribution of interferons i n humans. most of this work being restricted to animals. 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 (Priestman et al. 1982) or recombinant (Jablecki et al. 1983; ManlnO & Singhakowi nla 1984; Smith et al. 1985) Interferons do not readily cross the bloodbrain bamer Intact after in travenous. inlramuscular or subcutaneous administration. These data must ultimately be reconciled with the occurrence of neurotox ici ty. a common side effect of interferon therapy. Many studies have focused on the presence of nalural interferon in a variety of diseases, UnforIUnalely. there is no one review which collates this informal1on. The pomtlO be made is thai the presence of endogenous Interferon has been detected in tissue and flUids of a wide variety of seemingly unrelated 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 sclerOSIS. 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 expected, 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 humans. The catabolism of interferon-a, including subtypes, has been the most extensively studied of the 3 types. In general, a-interferons are filtered through the glomeruli of the kidney via luminal endocytosis 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 intact in the urine. Several studies have assessed the effect of nephrectomy on the pharmacokinetics of interferon-a: as expected, the clearance was significantly 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 interferon-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 (TokazewskiChen et al. 1983) the clearance ofinterferon-tJ, both natural (glycosylated) and cloned, was unaltered in nephrectomised rats; this finding suppons the hypothesis of a nonrena1 pathway for catabolism. Other organs, such as lung and muscle, have been suggested as potential catabolic sites for interferons. A more detailed review of interferon catabolism 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 proteins (Bocci \985a). Therefore, the clearance of interferons reflects the natural internal digestion and turnover of these proteins. The clearance of leucocyte 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 interferon 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 associated 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; Spiegel 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 interferon families. Adverse events of later onset include fatigue, anorexia and weight loss, and are often dose-limiting. The acute events, which include influenza-like symptoms of fever. chills, myalgias, headache, arthralgia and diaphoresis, usually occur within a few hours of drug administration and can often be ameliorated by pretreatment with paracetamol (acetaminophen). The severity of these events tends to increase with the

'95

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 injections compared with intravenous bolus administration, will result in an increased severity and duration of adverse events (Borden et al. 1988: Hawkins et al. 1985: Kurzrock et al. 1986; Thompson 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 fibroblast interferons induce fever through the stimu· lation of the hypothalamus to release prostaglandin E2 (Oinarello et al. 1984). Immune interferon appears 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 maintaining serum concentrations above an undefined threshold level (fig. 2) [Wills et al. 1984]. Similarly, a saturable induction mechanism has been postulated for immune. interferon (Brown et al. 1987). The threshold concept. along with the development of tachyphylaxis, provided the rationale for subsequent dosage regimens. Low doses were administered 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-

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I()6U dose of interfcron ....·2a given as II 4O-minutc intravcnous Infusion (0). an intramuscular injection (_ ) and a subcutancous 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 example, investigators reponed a positive dose response between elevated 1f2-microglobuli n and doses of interferon"'1" administered as 6-hour infusions (Vadhan-Raj et al. 1986), while other investigators using the same interferon"'1" preparation at the same dosage found no such relationship (Kurzrock et al. 1986). Olher investigators employing bolus doses, I-hour infusions, or intramuscular administration reponed no clear-dose response relationships using interferons-a, -If or "'1",

C/in. Pharmacokwe1. /9 (5) /990

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although some trends have been observed (Goldstein 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 doseresponse relationship involved interferon-
measured the resistance to vesicular stomatitis virus in vitro after collecting peripheral blood mononuclear 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 prolonged, continuous exposure to interferon following intramuscular administration was associated with a longer duration of 2',5'- activity relative to the same dose given intravenously, suggesting a dependence on ro ute of administration. Another notable 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 associated with a viral in fection are pan of the host antiviral response and are necessary for antiviral activity.

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Another consideration is the relationship of biologIcal response to serum concentrations. Seru m concentrations of interferons following a si ngle dose are generally nondetectable aHer 24 hours. The induced 2'.5'- activity, and other actions indUCIble by interferon, last several days. In the case of in terferon-~. 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 responses 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 interferons.

6, Drug Interactions Precedence for drug metabolism interactions between interferons and other therapeutic agents has been established in animal models. Work conducted in mice has shown that interferon-a (Parkinson 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 reduction in the level of microsomal cytochrome P450. Clinically. Williams and Farrell (1986) reported a 16% decrease in the clearance of phenazone (antipyrine) after a isngle therapeutic intramuscular dose of interferoo-a to 9 patients being treated for chronic active hepatitis B, suggcstinglhat interferon may reduce hepatic metabolism in humans. These same investigators assessed the interaction between a single therapeutic intramuscular dose of interferon-a and a single 5 mg/kg in travenous dose of aminophylline in 5 patien ts with chronic hepatitis B and in 4 healthy subjects (Williams 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

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 halflife 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 workshop and publ ished recently (Von Wussow & Borden 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 variables such as dosage regimens. roule of administration. cu mulati ve dose, length of treatment, and sampling time and frequency. and standardised antibody detection methodology. need 10 be developed or implemented to satisfactorily ans .....er the question of the clinical relevance of human interferon antibodies.

Ref erences

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JA C) t~thoc ~t ,nh'boioon a_) ror ,n ' trft1on:lI AG. Tht mle of surfan: nrboloydratC'S ,n llot he· Pltot r«Of,n'toon and lI-a nsp,m or t,rrlll'ton. Il)'coprott,n •. In Mt'st.... (Ed.' Ad~arK:n ,n cnzymololy. Vol. ~1. pp. 9&.128. 10hn Wlky & SonJ. New York. 197~ B,U~u A. cit Somtr P. Edy VG. ck Ckrrq E. Heremans H Humin fibtobllil ,ntriron for d,nocal Inillo: ph.rmKOl,,,,,u.... and 101· ...... bol .. y In upcnmmtai anunals Ind huma~ AntlmltTOboal "¥nts and Otemothtnp) 16: 1979 B,IIO T. Eckry H. ~kr A. Rownbo:'I H lnvoh'tnl(nl of lite kodM')' ,n (':ILllbo/,sm or humin kukocylt ,nterferon. Joumll or ~n."",1 V,roloey 59' 19-45. 198200 B,IIO T. Mlda. Z. ~nlcr A. Rownbc:fJ H. The: kod""y 1$ thc ma,n .nc of In lc:rkron dqradaUOlt . lou ....1ollnl...-f...-on Rneorcll 2: JOI. )()8. 19&2b B,crtc JR . L, nden JK. ~ M. Mltrt R Interkron ,n ...ctJOIt bhmr nutd from """""tIC: \n,onJ. 8nlt'" Jou ....1 or Dmn.Itoloty 101: 29).199. 1913 ~ V Doilnbuuoct. nuboh .... Ind pIIIrmacol"nnoc:s of Interfer. ons. In Finoa- ct al. (Ed.) In ''1''0 and (Ional fluoch. Vol . • . pp. .7-72. EIKYOtf. Ntw York. 198~ ~ v . Do francnro P. Pacon, A. """",, GP. Row GB. el at Re",,' Arm~tron,

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8oc:ci V, Mlun!.boch AB. M.... nwn fK. Autm.d,,,,,,phK demOll~11'I'ion ofhllman Il' l_in~rfnon alpha , 1\ 1):IOSOmesofl'lbbol pro. i m.ll l1bu~ a:Ul. Journal ofSubm~ C)'toio&>' 16: 153-157. 1984

80tti V. Motensoen KE. Musmtol. M. Pacini A . ..... Iou L. tl aI. Dqradal tOn of human 1U1.; nlerfrron aJphI by ' I(lLl.ed ~rfuxd

.. bbol kodMy and ">'n. Journal of ubon'QI'}' and 0,"1<;&1 Medl( , M 10 1; 131-36), 19S1b 8oo;ot1 v , Px,n. A. Band".. lh L ~na (i p. MU$«uo/a M. elaL Tho !'Ok of IIv" ,n 1M ca ... boI~ of hu ..... n ... and ,IJ..nl«frron. Jou.NIl of~,,",,1 V,fOIo&y 60: }97-400. 19th 80tri v , Paan, A. Musc:cn ola M. Pukw L Pns,na GP. ReMl 1M'ubol,,,,, 0( .. bbil Knlm in~ . loul'NIl of ~"",,I V'roiou H : 291.lO4, 1911, BottI V. !"K,n, A. Muocrn oLa M. ","","" L ~fII GP. eliL Rmal filll'Ilion. aboorpllOn and t:lubohfm of human alph.l Inlerftron.

'ou ..... ' of I nl~ Rnn rdl l: J.t7·1S2. l'li l b Bocci V. Pac,n, A. MutcenGia M. I'ns'M G P. 1'I1I1l'I1I L. et II. TM bd~y .. 1M ma,n lite of in~rkron <'I UlboIllm . Journal of Inlcrrcron

Rntl~h

2: )(19.)1 4. 19112b

800;c. V . PIe'n. A. Pus.na G P. Pa ulesu L

Muo«u OIa M. tt at Caof huma n . nterferon...,. Jour ....1 of Gene .. 1 V ......... y 66: 8111· 891 . 19Ub Bonkn EC. Ha... . ' nl M J. Slelalf KM. StOftr 8 M. SchltStl JO. tt II. O,noal and biolo&ical tlfecu of recombi .... nt ,ntem:ron.;f adm,n,,~ 'nll.. ~tllOUSly dally ,n pI\aJI: I lnlL Journal of Inltfftron Rnn~h 8: 35 7. )66. 1981 IIomtnuInn LO. Spqr:I HE. ()neqno*Sb ZE. Krown SE. Colburn WA_ Int .. venoul and Int .. mll_IIr pharmKOll;IMtlU of~­ binant It.. kocyle A ,nlriron. European J ournal of Cl,nlCal PMrmKOIc:cr 28: 46')....(11. 1985 Brown TO. KOfIItr J. ~ Ie.. Gobndo J. Bonncm EM . r l aI. A phatot I d.nica] tnal o/'rmJfTlbinanl DNA pm .... inlriron. Journil orO,nlC.1 0!Ic0I0&r S: 19().191. 1987 Budd G T. Buko .... kl RM . Miketo L Yen · Lltberman B. Proffiu M R. Phltot- I tna l o f U h..pure humi n lc:u kOC)'.e ,n'em:ron ,n h.. ma n mali' .... nry. CIlI('tr C'l>c: mOlhe .. py Ind Pharrna.roloaY 12: 39-42. 1984 O·Acq ui.,o R. M.." mln M . Hi eks T. Rubon S. H.. kinl w. t. II. A phatot 1 .nll of ,ntl"lprri'oneal recombo .... n. pmma·, nterferon ,n advlncW ov.n.n C1mnoma. Jou ..... 1o/'O'nl('ll 0nr0I0cr 6: 68~ 69S. 1981 o.~on HW. Sroli'G M. Robin""" J A. H'lI'nl PO. Wootton R. cl . 1. Com~"lIvr 'nt ..........1 phannarolt'nctlC1 of in~rron uo;,.. two lPf'Iy ,y,lems. Journal of In,"*"", R nn~h): 44)...4.49, 1913 Ikvr M. o.hl H. Yand~,k B. In1nftron ,n the InUm Ind ~ '.,. ....1 nu,d ,n ~'ltntl w,th muluplc totltrwo'ind 01. ..... nruroIos· 1('11 d lson;\m.. A(U. Nrurolo&i<'a Sc:Indl .... VI('l n IS2- 160. 1916 Ikvr M. Mrllb)1: OJ. Clart....Jcnom O. Immune ,nlerfrron ,n InUm Ind l)no ....1 n uKl .n ""'u ....1Ot<.I .nhnul .nd rc:la1nl d,oordtn. An nal. of lhe Rheuml1ic OoKlK$ 42: 672-616. 1983 Oonlrello CA . Bernhr1m HA. OuIfG W. lI: HY. Na..,bhushan TL t l II. Mcch.in"m of ~vtr ,nd..ccd by rffQmbonanl humi n ,norrferon. Journal ofO, nla l I n..... tiption 74; 906-911. 1984 0. 11111 YH . In,erkron : wnen tlich vr reinfa.chtt. en.ym . ,m m unoioI'tothe &su m munl mil ....... , monQlolonaltn AnukOptm. Journal of O lnlal Ootm,ury and O , nlCa] Bwxhem ,Wy 20: 901-914. 1982 CioIdm1M D. S,daIfK M. SlortI' BE. Bro... n RR. 0.111 SP. tt.1. Hu.... n btoIcJioC rtSpI)ntot mod,flatJon by ,nte'*ron ,n lhe .b5tna: of mao.u ..bIc: InUm t()nC'rntl"l'IORII'" eom~"uve.na! of ... tonotan_ fOUl and ,n.l"lVrnotls 'nterfttvn.;f -'M. Jou .....1 of.he NIlIO/IlII Calltt'" Inst"ute II : 1061-1068_ 1989 G=n J R. KIt,n RJ . Fno:dman_K"'n AE. In ... b>onal adm,nllt,,"o n of lalJll' doses of h~ .... n Inokory\e ,n ,crfrron for lilt tmtmetu of condylomata KUmlnlll. Journal of Inf«hou. DtKlK$ I ~ 61261 5. 1914 Grunbef& SM. Kempf RA. Ventun CL M,U:hell MS. Phatot I ."•.ely of m:'Om bonan' ..,.. ,nt.neron .. ven by fou r-hour infus,on. CaMer Re· totl~h 47: 11 74- 11 711. 19:117 Qu nerman J U. Fi M S. Quesada J. Hom,n, SJ . i.eviM JF. e, . 1. eR (om bi .... nt ..... kOC)' te A int.neru n: ph.irmKOk'M lIcs. Impe.dOK lok.. na: . • nd b,oIOl'( dTrcu in caMer ~lI~n.$. An nl' , of lnle .....1 Med,c,"" 96: S4~ S56. 1912 IIboh~ Sll~

JU . ROKnblum MG. ROO'! A_ Fnltothe HA. ~ JR. PhaflT\lC'Ok,M1ic: "IKIy of ~n .. lly pure .,...,n,erltron In cance. ~lIenls. Cancer RtlHn:h 44: 4164-417 1. 1914 H.wk,n. M. Hom,nl S. Konard M. Andtrson S. S",laff K. Ph.tot I U .IUllion of. Iynl hehc mutanl of tI-,n'erferon. Clna:. Rnc:.rch 45: 591""5920. 19., H .... kin. MJ . 80rdtn EC. Memn J A. Ed ...ards BS. BIll LA. el al. Com~nlOfl of'he boolotic: effects of.wo rtCOmbolllnt h~man ,n~ronl.lpM (.A.nd (0) ,n hJmlns. Jou .... l ofO,nocal 0nr0I· DIY 1: 221-226. 1914 Hm::manl H. B,lllIu A. The poIen".1 rokor,nt.nCfOflland ,n lerftron 9)7.972. 1989 anlqOIUIU In ,nflammatory d,KIIC.. Dnop Jabkrl, CK. PopIaek O . Howdl S. K'npbury D. C.ntell Ie.. HOIfIdote Intnovenous .nf.. soon. of ,urrftTon Neul"OiOlY H ; 141 _142. 1913 Jacobi L Hrmdon R. F~m.an A. Curl\rt' A_ Sm"h WA. to II. Mui.oo;enter doublc:..bhnd study of cfltt1 of ,nl.. tMally adm,nlSlered .... ' ural human fiblOblast in1nferon on tll«l'blllOIll of muh,pIe totltrwos. Lana:ll: 1411_141). 1986 Jonrs GJ. lin LM . Sofi:t y and loimoocr ofrt('Omb,nln' ,nltrli:ron alfa2to ( Rofrmn·AI ,n calOtt' ~I",nll, Clna:r 57: 1709-I1U. 1916 J onkman JHG . NICholson KH . FllTOw PR o Edtn M. G... mel./t' G . t t al. EIfCC'ls of ".,ntemron on 'KophylliM ph.. marokiM' 1U and mellbollsm. Bnus/I Jour ... ] of O ,nl('lll'llarmaroloay 27: ~S-80l. 1989 Kha n NU O. PulfOl'd KAF. Farquharson MA. HOWItson A. Stewan C. eo .1. T1Ic d,stnb,mo n of ,mmu.........,Uve 'nltl'frro.... lpha .n normal h~man ".....,., Immunolocr66: 201 -206_ 1919 K, nnula Y, M.nson K. Canltll Ie.. Phannarol'MtlO Ind 1O~f('lty of ,nhaltd human ,nttrferon ... ,n Pltltntl with IUIII ClrK:1:r. JOUrnal of Inltrferon RtlHrth 9: 419-421. 1m KUflroo:k R. Qo.onad.Io J R. Roso:nblum MG . Shc:Jwon SA. Gunerm.n JU . Phatot 1 study of IV adm,n,,~ rerombo .... n. pmma inlerferon ,n Cl IOttr PIIhenls. Ca _ TlUunent Rtpo", 1'0: (3)7. 1:164. G~nermln

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399

PharmacoklnellCS or Interferons

P'roum.n ..... P "'''MItOOI M. Jacobo SL Sur~nin. 01. Seh"'l1'" J. e ••1. Jmm~lIODdlom~lrJc as~l of I mcomblnanl h~man .lpha·2 Inlt'*ron ISCII )05(Xh JO~rNI of Clinical MlcmbtolOl) 22 ,96S99. 198' QUHad. JR . G~I1~rm.n JU. lIe"h E' 1 Clinical and Immu"olOilul SllIdy of bt •• Inl~rf~ron b) In1lllmuscular roule In pallCnl~ ,,"'IIh mtlas'a"c ca~r Journ,1 of In.~rfcron ReKuch 2. S91·S99. 1982 Qunada JR GUII~rmln It). (l,nlcal "lid) of ,",omb,nln. DNA.pro. dlK'td ltuloc)l~ In.erferon (do".. AI ,n.n In.(rmIIlCn'l<'htdult In ca~. pallen.~ 10<>,".1 ofN.nonal (',~' In ~I"ulC 7()- 10-11.1046. 1983 RId"'an'~1 f "".~nl""".G JxOOs S. OdC'n E AITnm( \1 (1 al PIlar· maco~""'''n of In,Mkron ,,·2b '" Mallh) >oIunl ....... Journal of Clinical Ph •• mxokit> :1: ~J!-'3S. 1981 Rnl"dba", A Pnlh S Inlerferon~ prOleln " ......" ••. In &tOn e. al I[d.) T"" In.rrfrron .)"em. PI> 1~9-I68. L:n"cnI') oI"Tna, rrn.. Auliin . IQU Kosenbc"rt II Madar f . G.nlc. A. Rub,n""n \1 . 8ono T The file of Il' I.laborlltd human leukoc).~-<1erl\ed .Ipha In,.rfcron In the "... Journ.1 of Inl.,feron ReKa~h S: 121·127. 1985 Rull,ns",n" Fam,lIcl1' PC'. P"l~a S. Con"n ltnl aslOl) for In,.ncr· ons Journ.1 ofVlfOl"ll 11: H5.158. 1981 S,lon(n II. CiiF and I<'.um ,n.. rferon In mulhplc "deros.s, lonl,'uoIun ...•.." II o. •• rmlnillon of mInimal cfT«."c .nd JOItnobk dose Journ.1 of Inf«tIOUS 0.""31 .... IlO: 181·188. 198' s,m. G. ""rt",.("("k \I . fl&lln II. Ardalln 8 PhI"" I "ud) of fm)m· boMn. SoC. 17 ,nlMkron In lhe 'K1I1I1Cn, ofnonttr Cana, Trea.· mcn. RcPOfl s 10c 1J6S·1172. 19M S«,"",r 1>5 ImmunoradlO1I1Cln<" aUl) of hum,n ltuklX)l( InocrktOn u"nl monockmll .nllbody, Na'UK 290: }()I.}()). 1911 S«or J. Se~nl .. S, EfT«. of rn'Omblnanl ".Inltrl'eron on In ''''0 and In ~uro marl ...... of dru& m... abohsm ,n mK't. AI!sI1K' no. 298. H~paIOIOl) 4 1081. 1984 Shah I. Band J. s.amson M. Youn, J. Rob,nson R. (I II, ~rmaoo­ k'n~II" 100 IOIe",nce of Inlrll"CnoU' Ind In l nomu~ula. rn'Omb,· n.n' Ilphl·2 In'trfcron In pallen .. ,,"'IIh mlh,nant'" Ammcan JourMI of HcmllolOly 17: 363-37 1. 1984 SMN'ln SA . Knos. JA. fron S. Abram. !'G. foon KA . . . .1. A mul· IIp1r-
bIT".

2~1.24b6. 198~

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Smnh RA. ",n&\but) 0, ",Il.".. J. hmn H Cantril K o. .. nbuioon of In ...... ron ,n cnebo-mplnal flUid s)~.. m ... ,n.fJ.hcal. and ,n'no"enlrl(ular adm,n,,,not,on. Annal. of NeurolQl) Il. 81. 1982 Smuh RA. Norns f. PlIlmn D. B
.fIe,

Spoqcl RJ Inlron A (Intm... on Ilfa.2b~ d,n ... 1 Oven',,'" Ca""". Trrllmenl Re~ .. ws I ~ (Suppl. 8~ 5--16. 1985 Ta)lor G . M.no(lno Ill . M~ JA. Gurley v. 81a~hke J f . Inteneron rrdlKn ""pa'l( d ..... mtlabo!ism In VIVO In mo«. 0....1 Melaboll.m and d,sPOS",on 13, 4S9-463. 198' T hompson JA. Co. WW , llnd,",n CG. Collins C. Neraa. KA. el II. Subcullnrous !'!'COmbon.n. pmma ,""neron In ca~. pal",n'lI: touc"y ph.. mKflklncll .... and ,mm unomodull1Oty eITee... Cance. ImmunollllY and Immuno.hcnopy 2S: 47.'1. 1987 Tol..a'(""'",,.('''''n SA. Manofino Ill. S,.bbonl N Eft«11 of ncphm:. .om)· on ,he phlrmac:ok,nc,,", ofvanou ••1oncd human 'nl~rfcron. ,n ",IS Jounl.ll of ~.marollllr and E.pcnmenlal ThcnoPCUh", 227; 9·IS. 198) TurnC1" RB. Ourun FJ . Albr("("hl J K. Cnond.all AS. Saf,,)'.nd JOItno""" of ocular admln",nollOn of m:ombonan' .I~ ,n,crfcronll: Anh· m""oboal Aeen" Ind CheIl101,"",nopy II 196-197. 1989 Vldh.n.R~ S. N..... n C F.Shcro-,n SA. Or:lIeen HF. KfOYIn SE. Pha"" I lnal ofmcomb,nanllnl.mron pm ..... II} I·h. 'v InfusIOn. Canttr Trrilmcnt Repons 10: 601).614. 1986 "aoo der 8urt M. Edelste,n M. Gerlll L Loan. CM. HIIVhl MN. c. II. Reeombtnln. InlCrf~ron..,. (Immuneron) 4..272. 1985 ""Icck J. Gnoy PW. Rlndcrl nech. E. Inlcneron1l'mma: Ilympholme for.1I seIsons. In P«k (Ed,) Lymphok,nrs. Vol. 11. pp, 1·32, AC· a1kmlC. Orlando. 191' Von Wussow P. Bordtn EC. An1lbod ... 10 Inlnftronl'~ pa,~n .., dc· finln. lhe" .. "nfino~ JourNI of In .. rfcron ReKI .. h 9 (Suppl I~ SI.'72. 1989 W.ll ... J R. N. . J. Scott GM. S«k ... !>S. ImmunondoomclnC 'Hil of Otr\Im Inltfftron UII"l a monodof>ll an"bodl Jou""lof Genenol V,fOIo&y 62: 181·18,. 1912 Weill RJ. Week pl(. Bothntr RL Knvn W. Rane~ 11. 8. tt ,I. I~ur' feron ,n ",",kim! wnh 1KUrrml ac:ult IymptMx}l1C INl emlL I phaSoC I "00) of pharmacok,nc,1CS Ind lOIrrana. JOUrNI of In.t'*ron R..... ~h 8 )()9.JII. 1988 Wdl",m. SJ. F.mll GC. Inlllb",on of .n"p)n:nt mClaboh~m b) In· terfC1"Qn 8",lsh Jounl.ll ofCbn ... ) Pharmarolo&Y 11: 610.611. 19U W,lIoam. SJ. &lriI·lImbcrt JA. famll GC. Inh,b,t,on oftheophylhnt mC"'bollsm by,nltrferon linen 939·941. 1987 W,II. RJ. o.n",. S. SplC$C1 HE. G,bson OM. Nadltr PI Inlerferon kt"..,,", Ind .(he...... re.CllOns after In'1"I>'(IIOU'. ,nlrlmu~ular and lubculantOU. ,n.l«"on Clinical Pharmao:olOl)' and T""noPt'~II", lS: 722.727. 19i4 W,II. RJ . Sp....1 HE. ConllnlM)u, Inlno"'nous ,nfuslOn pharmlot"Olc rnporISoC (In'1\".nol) 10 m:ombo",nl hUnl.ln ,n.mtronl alpha Za IS I funct.on or dose and rou,. of Idm,n,"",,,on ,n Malthy volun· I«rs. Chnocal f'IIarmao: .....Y.nd T htraPCU11CS 42: s('7·S75. 1987

..,.on

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

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